Integration of a Single-Use Platform Process within an Innovative Facility Design

With the age of the blockbuster drug passing, the business model for the biopharmaceutical industry is changing. The personalization of medicine, the emergence of biosimilars and biobetters, and the need to provide vaccines globally are just some of the factors forcing biomanufacturers to rethink how future manufacturing capability is implemented. One thing is clear—the traditional manufacturing strategy of building large-scale, purpose built, capital-intensive facilities is not going to meet the industry's emerging production and economic requirements.

Single-use technologies have the potential for helping companies execute their developing strategies for flexible manufacturing. The adoption of disposables continues to increase year over year and is already established in many process steps within the industry. The benefits of single-use technologies, such as reduced cleaning and validation, reduced downtime, and reduced equipment footprint, are well recognized and continue to drive the development of new and innovative products. Over the past decade, manufacturers have witnessed the progression from disposable encapsulated filters and tubing sets for small-scale production to today's 2000-L bioreactors and 2500-L single-use mixing systems in licensed biomanufacturing processes.

A fundamental change in the way biopharmaceutical facilities are designed and constructed is required. The pressure to reduce facility-investment costs and the cost of goods manufactured is a primary driver in the paradigm shift occurring in industry's approach to facility design (1). Innovation is required to design facilities that are more flexible, more rapid to construct, less capital-intensive, and can be repurposed as product requirements change. The new facilities must be of high quality and rapidly reach compliance after construction. New facility concepts and products from suppliers are beginning to emerge that anticipate the unmet needs of the biopharmaceutical industry, as are the expertise and innovative thinking to meet the challenge.

This article discusses how a single-use manufacturing process for a monoclonal antibody (mAb) can be integrated into self-contained modular cleanroom systems, such that a total "out-of-the-box" solution for manufacturing capability can be realized. Overviews of both the process and facility elements considered as well as the related advancements and enabling technologies now available are provided.

A conceptual integrated design is presented that can be used as a blueprint for the next generation of biomanufacturing facilities. The benefits of this approach with respect to flexibility, cost, and schedule are discussed. The concept presented here can be applied to other biopharmaceutical manufacturing processes and facilities, including, but not limited to, vaccine manufacturing, multiproduct/multiprocess capability, and clinical manufacturing.

THE PROCESS

The development of technology platforms is an approach that is becoming more prevalent within industry today. The ability to use platforms to standardize upstream and downstream biopharmaceutical manufacturing processes as well as analytical methods has the potential to significantly reduce the time and costs associated with bringing a product from development to commercialization. Platform cell lines and expression systems have been successfully implemented in upstream processes by a number of biomanufacturers. Companies such as Bristol Myers Squibb are developing antibodies and other molecules by applying platform-based approaches (2).

The standardization of processes logically drives the standardization of process equipment and technologies. An equipment technology platform can, therefore, be engineered for a process and used as a basis of design for similar molecule types, such as mAbs. This template provides a starting point that can save significant time and effort during the engineering and operational design phases in the product lifecycle. Implementation of single-use technologies within a platform can further reduce the project timeline for establishing manufacturing capability.

SINGLE-USE PROCESS DESIGN

The continued innovation and availability of disposable technologies now allows for the design of complete single-use unit operations that can be combined into single-use manufacturing process platforms. Companies such as Sartorius Stedim Biotech (SSB), have engineered generic process platforms by using disposable technologies within its own broad product portfolio. SSB's Process4Success platform is currently established for mAb processes across a range of batch sizes and product titers. With the exception of the resin-based chromatography technologies used in the downstream purification process, SSB's platform incorporates complete single-use technologies for all unit operations through bulk filling and controlled freeze/thaw.

For the purpose of this article, the discussion will focus on the conceptual design for a 500-L starting batch size. Table I summarizes the process steps and equipment/disposable technologies for the upstream process and downstream processes as well as the support process operations. For the Chromatography I and II steps, any manufacturers' column, resin, and skid, as defined by the customer, can be integrated.

Table I: Single-use platform process.

The Process4Success platform is designed to be used as a starting point for working with a customer and can be modified as needed to meet a customer's specific process requirements.

THE FACILITY

The development of facilities for biopharmaceutical production has been met with certain challenges in the past. In some cases, the process constrained the facility design, and in others the facility constrained the process. Variables such as total volume of space, classification requirements, and decontamination, among others, were part of this matrix. With the advancement of totally modular, autonomous cleanrooms, and single-use technologies many of these problems can now be addressed. Higher yields and more targeted market focus have also lowered the total amount of material needed to serve the marketplace.

Facilities need to be designed to meet some if not all of the following requirements:

• Lower capital expenditure

• Provide a platform for rapid transition between product development and commercialization

• Provide rapid start-up and ease of compliance

• Be reusable and flexible as process and products change.

No longer can companies afford $500 million facilities expenditures that are locked into only one product and that will have to be abandoned or scrapped after the production capacity is no longer required. The idea of using a totally autonomous, flexible, and reusable cleanroom serves as a basis to address these requirements if designed with the following features and attributes:

• Procured (and depreciated) like process equipment

• Easily movable

• Easily integrated into the host facility and process systems

• Requires only basic gray space

• Able to be decontaminated, recommissioned, and re-used

• Addresses all normal ranges of classification

• Self-contained heating, ventilation, and air conditioning (HVAC) and filtration.

THE POD APPROACH

G-CON has developed a series of autonomous cleanrooms or "pods" that meet these criteria. The typical pod is 24' x 42' and is transportable to the facility site by flatbed truck in two 12' sections. The pod forms a large working space of over 760 ft² and is shown in Figure 1.

Figure 1: The interior of a G-CON pod.

The pods are equipped with air bearings and can be moved into place effortlessly as they "fly" on a layer of compressed air. No special rigging is required to move the facilities into place within the gray space. Process piping is completed at the factory and process equipment can be pre-installed at the factory or at the site. The utilities are connected via umbilicals with quick connectors to a service chase as shown in Figure 2. Services such as water-for-injection (WFI) and USP water are prepiped into the pods and provide the required zero-dead volume drops.

Figure 2: The exterior of a G-CON pod showing the utilities connections.

The cleanrooms are typically attached to an access corridor to provide an interface to the building and provide another level of pressure cascade for containment. Pods have on-board inlet and exit filtration in addition to the HEPA filtration in the workspace, which effectively isolates the cleanroom from the gray space and allows the pod to be used in either positive or negative pressure modes and in constant volume or variable volume mode. Pods have on-board fire suppression so that hard connections to building sprinkler systems are not necessary.

Materials of construction are consistent for use with and resistant to the major disinfectants and decontamination systems including vapor-phase hydrogen peroxide. Pods are also equipped with a complete and robust control system featuring Rockwell Control Logix PLC controllers with additional digital input/outputs. All sensors and control systems are internet protocol (IP) addressable. The pod is connected to the local area net work via Ethernet and a single cable connection. I/O protocols are provided to the recipient and facilitate the integration of the environmental monitoring and control.

A PROPOSED MONOCLONAL ANTIBODY FACILITY CONCEPT

With the palette of features designed into the pods, innovative facility designs can be realized to address most pharmaceutical process challenges. Figure 3 illustrates the application of such technology to a typical mAb facility equipped with Sartorius' Process4Success single-use process platform technologies. The facility combines the use of gray space to house and service the classified area and more traditional "stick-built" areas to serve as support space.

Figure 3: A monoclonal antibody facility equipped with Sartorius’ Process4Success single-use process platform technology.

This arrangement features a "ballroom" type approach to pod topology developed in a 32,000-ft² class A warehouse-type structure. The upstream pod houses two BIOSTAT CultiBag STR single-use bioreactors and support equipment such as a biosafety cabinet, incubator shaker, BIOSTAT CultiBag RM seed reactor, and FlexAct CH system for primary clarification and filtration. Buffers and media are produced in conventional rooms on the south side of the plan using Palletank and Flexel Bags for mixing and storage and then transferred via a controlled nonclassified (CDC) corridor to the primary materials air lock (MAL) that services the Class D working area within the cGMP envelope.

Once the cells are expanded and production of the mAb is accomplished in the 500-L bioreactor, the cell mass is filtered out and transferred between pods using the Biosafe Rapid Aseptic Fluid Transfer System (RAFT). The downstream pod is equipped with a typical three-stage capture and chromatography system for mAb purification as well as the required virus clearance steps performed with the FlexAct VI and VR systems.

This particular design serves the purpose of also integrating a syringe filling operation as part of the process integration. Two pods are joined together to provide a space for a modular sterile syringe fill system. The Class D corridors serve as personnel air locks (PAL) and MALs for moving large amounts of packaging and filled materials into and out of the Class B workspace surrounding a Class A cabinet based fill system. An inspection and packaging pod is the final step in the cGMP envelope before transferring the product to shipping.

ADVANTAGES

A cost analysis was made by an outside engineering firm to compare hard costs between the pod-based design and an equivalent stick-built or modular hardwall cleanroom system. The cost savings on the total project was found to be greater than 30% for the pod-based design. The largest savings were in HVAC costs, utilities distribution costs, and superstructure costs.

Because the facility can be built in a generic building using pod technology, developers will consider financing the construction of the shell using a lease-back financing model that relieves some of the capital burden. Costs savings on engineering, construction supervision, and savings in QA costs by employing premanufactured autonomous cleanrooms are not reflected in the capital expenditure savings.

The opportunity cost is greatly enhanced because the process portion of the build is being completed in parallel, not iteratively, to the shell and support space. This should in most cases deliver a functioning facility to the user in less than 18 months.

INTEGRATION OF PROCESS AND FACILITY

Systems integration is one of the key elements in the start-up and on-going development of any facility. The future integration of process analytical technology, electronic batch records, and electronic inventory control are all features that should be iterative and not retrospective in any design. The autonomous clean-rooms are already equipped with all of the computing power and I/O structure necessary to interface into process integration and manufacturing execution (MES) solutions, such as Rockwell Automation's Factory Talk and PharmaSuite applications. The systems are built on modules of prevalidated software and are configurable to the multiple disciplines and needs of the bioprocess industry. An example of this type of systems architecture is highlighted in Figure 4.

Figure 4: Systems integration architecture.

CONCLUSION

Flexible environments and flexible single-use systems have eliminated many of the classical constraints on biopharmaceutical processes and have allowed designers the ability to design modular bioprocesses and easily house them in properly classified environments. The ability to repurpose, improve, change, and re-use these core elements of a facility, affects the industry from large pharmaceutical to small biotech companies. Whether planning new facilities, establishing first time manufacturing capabilities, or executing new supply chain strategies by decentralizing manufacturing, companies now have new options to consider. And as suppliers continue to develop innovative products and collaborate effectively, the closer the biopharmaceutical industry will get to achieving its future manufacturing strategies.

R. BARRY HOLTZ, PHD, is president of G-Con Manufacturing, College Station, TX, bholtz@gconbio.com, and DENNIS POWERS is director of integrated solutions, North America, Sartorius Stedim North America, dennis.powers@sartorius-stedim.com.

REFERENCES

1. K. L. Nelson, "Single-Use Technologies and Facilities," supplement to BioPharm Intl . 24 (11), s22–s28 (2011).

2. E. Greb and A. Drakulich, Pharm. Technol. 36 (3), 46–50 (2012).