Perceptions and Considerations for Adopting Closed Processing

Closed processes that incorporate single-use technology offer advantages in the areas of flexibility, speed, quality, costs, and operations. A reduction in complexity enables increased facility flexibility and efficiency as segregation does not rely upon the surrounding manufacturing environment and operations. Facility flexibility is especially critical in the case of multi-product facilities, which is a growing trend as cell, gene, and other advanced therapies have expanded the industry’s pipeline.

In this dynamic environment, manufacturers must move rapidly to manage multiple, complex product pipelines and successfully scale processes. The growing roster of therapeutics and vaccines also sets the stage for modular, connected, and ultimately, continuous processing. Closed processing is one in which physical barriers segregate the process from the external environment and materials enter or leave the system via designated control points.

Modular facilities overcome the challenges presented by conventional brick-and-mortar production sites. They offer flexibility to rapidly change or expand the facility responding to fluctuations in demand, new products, or multimodal activities and platforms.

This paper explores key benefits of modular facilities and closed processing, including the impact on product protection, declassifying spaces, site agnostic multiproduct manufacturing capability, rapid mobilization of small scale, localized, bioproduction manufacturing, and mitigating regulatory risk assessment concerns.

The definition and impact of closed processing

While the adoption of single-use technology has expanded throughout the biopharmaceutical industry, process closure has not been as rapidly incorporated.

Closed processing can be considered a logical extension of the single-use technologies leveraged for biopharmaceutical manufacturing. Physical barriers separate processing fluid from the external environment, including the operators, and materials enter or leave the system via designated control points. While closed processing does not equate to sterility, it does imply that the initial bioburden level is maintained—reaching a biostatic state.

A functionally closed process system, as defined by the International Society for Pharmaceutical Engineering (ISPE) and the Pharmaceutical Inspection Co-operation Scheme (PIC/S), may be routinely opened (e.g., to install a filter or make a connection), but is returned to a closed state through a sanitization or sterilization step prior to process use (1, 2). A closed system may also be a system (e.g., a single-use bag pre-sterilized with aseptic connectors for transfer lines) that has never been exposed to the environment and materials introduced go through an additional process that avoids exposure of the product to the environment. Closed processing does not imply a sterile process, but rather prevents the ingress of undesirable materials into the process stream.

Three criteria are used to define the readiness of a single-use closed system:

• Initial material cleanliness: the level of non-viable chemical or particulate residue in the path of product flow
• Degree of equipment integrity: the system’s ability to prevent barrier breaches and microbial ingress across all components before and during its processing life
• Bioburden: the level of viable microorganisms in the product and their capability to grow.

Achieving a bacteriostatic status is the goal, where no additional bioburden is introduced in the system. As closed processing is more widely adopted, the potential benefits are clear (Table I).

Product safety and protection as a main driver of closed processing

Upstream operations and manufacturing (fill/finish) are intrinsically axenic and sterile operations, respectively. Harvest and purification operations, however, do not need to be sterile, but need to be performed under low bioburden conditions. The possibility to run these processes under low bioburden conditions has decreased the motivation to implement closed concepts, even if the process and facility operations would benefit.

When using a closed process, risk of contamination is reduced due to the physical barriers protecting the product from the primary source of microbial contamination—human contact. It is a common misconception, however, to associate the idea of system closure with an aseptic environment. A sterile process is intrinsically closed; however, not all closed processes are sterile. By design and use, a closed process maintains a bacteriostatic operation. A closed system may contain low bioburden (e.g., chromatography column), where the allowable (detected) bioburden level needs to be defined at a process step level.

Some process steps need to be sterile (e.g., media transfer to a bioreactor) to prevent the occurrence of contamination. Others such as viral filtration may be operated aseptically without a validated sterility claim, to mitigate business risks such as regularly scheduled revalidations and tedious and expensive investigations in the case of a deviation.

Closed processes allow the end user to de-grade the clean rooms that host those processes (e.g., European Medicines Agency [EMA] Grade C to Grade D), with significant economical and operational benefits. Room de-grading, less frequent environmental monitoring, potential avoidance of dynamic environmental monitoring (EM), de-gowning personnel, and eliminating airlocks are some opportunities resulting from closed processing.

EM deviations can be costly and time consuming for a manufacturing site. EM in lower classification spaces has less strict requirements and limits in static and dynamic conditions. For some clean spaces (e.g., controlled not classified [CNC]), environmental requirements are not defined by international standards, and it is up to the user to define them. Less stringent requirements in lower-grade spaces reduce the probability of environmental deviations and the impact on the batch being manufactured (e.g., to be re-processed or discarded).

Assuming closed processes are in place, a lower-grade suite not only makes the work environment more comfortable for operators and saves time in gowning/ de-gowning procedures, it aids in detection of exogenous contamination events. For example, if a cell culture operation is performed under a lower-grade production area, any potential contamination (however unlikely) would be of greater scale and therefore be more detectable. This detectability enables earlier response and action, saving days invested in cell culture of a failed batch. In contrast, if the same operation is performed in a higher-grade production area it will take longer for that small contamination to be detected. The likelihood of contamination in both scenarios is the same, but the detectability is greatly enhanced in the first scenario.

Process closure not only affects cleanroom equipment, but also requires closure of any incoming material and/or utility streams (e.g., water for injection [WFI], buffers). Closure of incoming streams may be achieved by bioburden reduction filtration, the use of aseptic connectors, or by any other closure procedure (e.g., sanitization).

Closed-system processing with single-use technology is an attractive option for biomanufacturers:

1. Operating continuous processes for many weeks at a time where the build-up of bioburden within equipment must be avoided
2. Producing vaccines or biotherapeutics in response to an outbreak or pandemic, where facilities may need to be rapidly constructed or retrofitted in areas where infrastructure and utilities are limited
3. Manufacturing multiple products in a single facility.

Industry perceptions of closed processing and its benefits

A survey conducted by CRB revealed a large percentage of pharma companies are exploring closed processing with the top driver being (3):

• Reducing the risk of contamination by separating the product from the environment and personnel
• Accelerating time to market due to reduced infrastructure requirements
• Enabling synergy of single-use technologies and fail-safe aseptic connection to close processes.

Survey respondents perceived closed processing as being most beneficial for modalities which typically rely on high room classification for product safety. For vaccine manufacturing in particular, certain modalities (e.g., live virus vaccine) are not compatible with a final sterilizing-grade filtration step and as such, many manufacturers have turned to closed processing.

The traditional “Facility of the Future” concept was derived from production of therapeutic proteins and had limited biosafety requirements. The industry sought to achieve all process unit operations in a single continuous open ballroom with lower (Grade D or CNC) environmental classification, achieved by process closure. Facilities gradually implemented the concept with greater degrees of process closure, requiring less facility control. While open process steps have been greatly reduced, they are not eliminated (Figure 1, left). Modern facilities employing this strategy have some of the following qualities:

• Large-scale operations
• Single product manufacturing
• Process closure to segregate batches and campaigns, carry-over risk mitigated with clean-in-place (CIP) and/or steam-in-place (SIP) procedures
• Bi-directional material and personnel flows
• Separate ballrooms for pre- and post-viral filtration of adventitious agents
• Separate room for bulk product filling (often performed as an open operation within biosafety cabinet)
• Separate room for column packing.

For cell and other novel therapies, processes are largely carried over from pre-clinical work performed using open operations. As such, these processes need to incorporate process closure techniques to their design and adoption in their transition into commercial manufacturing. With gene therapies, the above stated drivers require facility level controls beyond what the traditional “Facility of the Future” offered. Cell, gene, and other advanced therapy production facilities often have the following qualities:

• Small scale (approximately 2L–2000L) operations utilizing single use equipment
• Multi-product manufacturing
• Varying degrees of process closure
• Unidirectional material and personnel flows
• Separate rooms, as needed, to segregate pre-viral from process steps from post-viral transfection process steps
• Separate room for bulk product filling (often performed as open operation within biosafety cabinet)
• Separate room for inoculation activities
• Separate ballrooms for pre- and post-viral transfection
• Multiple production suites, each accommodating a separate product.

Whereas traditional biotech production had scaled “up and in” (i.e., large scale with centralized production) by utilizing large vessels and centralized manufacturing to create economies of scale, cell, gene, and other advanced therapies must scale “down and out.” These therapies often lend themselves to utilization of small equipment and processes in identical and repeated installations to achieve scale. The creation of a standard repeatable process-based element (module) is an important step to effectively design and manage these facilities. Modularization must begin with a thorough understanding of the process equipment and unit operations involved; this is critical to efficiently scale out operations through the clinical stages of development and into eventual commercial-scale operations.

The combination of off-site pre-assembly of volumetric modules and closed processing offers the possibility for multi-product or multi-modal concurrent manufacturing of products requiring BSL-2 and greater containment. The nature of off-site pre-assembly allows for tighter construction tolerances and the opportunity to factory acceptance test (FAT) an entire production suite. This facilitates the commissioning, qualification, validation, and operation of complex pressurization schemes desirable to prevent cross-contamination between suites and/or specific unit operations. It also sets the stage for connected, or even continuous processing, increasing overall facility utilization and throughput.

From closed unit operations to modular manufacturing space

While production of therapeutic proteins evolved to scale “up and in,” the evolution of advanced and personalized therapies requires technologies to produce numerous smaller batches, and in some cases, be located close to the patient (i.e., cell therapy). As demand for small scale, localized, temporary bioproduction manufacturing close to patients—including places where local infrastructure is lacking—the industry will likely rely heavily on the advantages of closed processing at both the equipment and facility level.

To this end, facilities of the future will be purpose built and multi-modal in design with the ability to host different products and fit different processes. This contrasts with the historical approach of shaping the building to the product.

Closed processing and modules give the opportunity to have a late process development while not delaying the facility design. The modules can be hosted in the facility and switch between activities assigned to them (e.g., upstream vs. downstream) based on needs (e.g., volumes, flux). The modules may be equipment and process agnostic work-cells.

Modular design may be considered a next step following single-use equipment platforms, applied at the facility level. Single-use equipment is typically mobile in nature, allowing the user to rearrange equipment and processes. Continual re-arrangement of equipment locations (and subsequent utility loads) disassociates traditional design assumptions and causes a challenge for the typical facility designer, as there are too few constraints to provide clear design direction. The solution is to provide a standardized set of utility use points at each potential process unit operation. While every use point may not be utilized at the same time, each will very likely be utilized over the lifespan of the facility. This concept of standardization is the driver for a modular design block approach, also known as equipment “work cells” (Figure 2A). A single work cell may be designed for several different environmental classifications and/or utility loads in case a new product or process is implemented in the future.

Similarly, off-site pre-assembly and modular delivery may be considered a logical extension of closed system processing, applied at the facility level. Several modular clean room (MCR) manufacturers originated with high level biosafety (BSL-3 and BSL-4) containment laboratory designs and the concept of an “isolator which people can walk into” (e.g., Germfree and Extract). Off-site pre-assembly in a controlled environment allows for tighter construction tolerances than are typically achieved with on-site construction. These tighter tolerances result in less air leakage than would occur in a traditional stick-built or panelized facility, allowing for better environmental control around critical process operations. This degree of closure has been leveraged for secondary containment of bio-hazardous materials for well over a decade. Advanced therapy and personal medicine manufacturing, which often requires BSL-2+ containment, has started to apply this same advantage but towards protecting product by reducing the potential for cross-contamination.

Even though it may be technically feasible to provide all unit operations in a single room utilizing closed process equipment systems, most end users adopt at least some level of segregation due to a variety of factors including:

• Processes requiring BSL-2 or greater containment
• Reducing cross-contamination between multi-product or multi-modal operations containing open process steps
• Perceived cost to implement a closed process (e.g., emphasis on first cost instead of life cycle cost).

Factors such as corporate standards, legacy standard operating procedures (SOPs), and/or mitigation of a perceived risk may have an impact on facility design and operational features without being critical in achieving process closure.

Once critical risk-based process segregations are determined, the impact of introducing facility level segregations to enhance process cadence and production throughput may be considered. In cases involving the factors listed above (BSL-2 and/or open operations), there may be an advantage to provide additional facility segregations to allow separate batches or campaigns to occur with greater frequency. This approach reduces the number of unit operations within a physical area so that line clearance and introduction of a new batch may occur sooner than in a traditional ballroom approach. This is especially true for multi-product operations where a second product may follow the initial product with greater speed. This prevents equipment from sitting idle, improves equipment utilization factors, and improves overall facility throughput. A closed process achieves this goal to the greatest degree.

When standard modular design and delivery are utilized concurrently, the result is an ability to provide closed, connected (and ultimately continuous) processing at the facility scale. Each work cell may be used for a variety of process unit operations; multiple work cells are grouped into a physical MCR which may be off-site pre-fabricated and pre-assembled (Figure 2B).

Process driven segregation needs should define the final structure of the MCR and/or interconnections. A single area of process segregation may be much larger than a single MCR. Multiple MCRs may be connected to form an operational suite of appropriate size or scale. The MCRs in each suite may be combined in several ways to achieve a containment suite using multiple segregated MCRs (Figure 3A) or a ballroom using closed processes and multiple connected MCRs (Figure 3B).

The adoption of standard modular design and delivery may be considered a logical extension of the critical success drivers for process closure as outlined in Table II.

Conclusion

The benefits of combining modular facilities and closed processing are clear and include increased flexibility, speed, and quality, along with life cycle cost savings due to operational risk mitigation and operational efficiencies. With the growing number of therapeutic modalities driving the need for multi-product facilities, interest in this approach to facility design and manufacturing workflows will undoubtedly gain momentum.

To help ensure success, evolving to a fully closed process should be undertaken in a stepwise manner. As a first step toward implementation, unit operations should be closed within the existing facility. This approach involves modularization of the process followed by modularization of the facility, if required for multi-product manufacturing. The final and ultimate step would be to operate a new facility with modules and/or a fully closed process.

References

1. ISPE. Baseline Guide Volume 6: Biopharmaceutical Manufacturing Facilities (Second Edition), November 2013.

2. PIC/S. Guide to Good Manufacturing Practice for Medicinal Products, Part II. Feb. 1, 2022.

3. CRB. Horizons Reports. Crbgroup.com (accessed March 30, 2023).

https://www.crbgroup.com/horizons-reports

About the authors

Jérôme Dalin is BioContinuum Strategy Development—Senior Consultant, and Sarah Le Merdy is Systems and Single-Use Global Strategy Deployment Manager, both at Life Science business of Merck KgaA, Darmstadt, Germany.

JP Bornholdt is Director, SlateXpace Technical Operations, and Alejandro Kaiser is Senior Process Engineer, both at CRB.