Building Better Manufacturing Facilities

In adding manufacturing capacity-whether through new, greenfield sites or by refitting existing spaces-biopharma and pharma companies seek flexible and efficient production. Getting a facility up and running quickly with a tight budget is increasingly important. 

Flexibility is crucial in biopharmaceutical manufacturing, because companies increasingly have multiple modalities (e.g., monoclonal antibodies, cell therapies, and gene therapies) in their pipelines. New biopharma facilities often use single-use technology, and modular buildings and systems are becoming more popular. 

“The biggest challenge is to map the current need for flexibility in manufacturing processes to the facility,” says Stefan Kappeler, technology manager for life sciences at Exyte. He notes that facilities must be prepared for changes in process flow, in scale, and in manufacturing technologies.

Flexibility is important in oral solid dosage drug (OSD) manufacturing, as well. Manufacturers are seeking to “right size” their operations and capacity based on their product portfolios and to upgrade processes, equipment, and technology for improved efficiency and faster product changeovers, notes Dave DiProspero, director of pharmaceutical process technology at CRB. Improving equipment and facilities for product containment and cleaning operations are other active areas in OSD, he adds.

An ongoing drive toward closed processing simplifies facilities and allows lower room air cleanliness classifications, which corresponds to savings in capital and operational costs, adds Eric Bohn, partner at JacobsWyper Architects. Similarly, the smaller equipment associated with continuous processing and the smaller-scale processing associated with advanced therapy medicinal products (ATMP) result in smaller production suites that are easier to support and operate, says Bohn. “Facilities are being more closely tailored to the needs of the process,” he notes. 

Renovating facilities

In the past year, multiple life-sciences companies have updated or expanded manufacturing capacity by renovating existing facilities. GlaxoSmithKline (GSK), for example, completed a retrofit of its Rockville, MD site in October 2019 that increased capacity for its injectable drug Benlysta (belimumab) and involved demolition of existing suites and installation of new equipment (1). The company also renovated its Upper Merion, PA site and updated laboratory and manufacturing capabilities, including adding single-use bioreactors (2). A nearby, former GSK facility is being transformed into The Discovery Labs biotech campus, which announced in January that it would be the home of The Center for Breakthrough Medicines, a new contract development and manufacturing organization for cell and gene therapies (3). 

Renovating an existing facility can save time compared to a greenfield site, where approvals can be complex and potentially last a year or more, says Bohn. Although renovations typically have costs for demolition, waste disposal, and the need to bring roof structures up to current building codes, for example, a significant cost savings is often found in site infrastructure, he notes. 

“The most common refurbishments we see are from mothballed facilities,” says John Noble, vice-president and general manager, life sciences, at Jacobs. “If you can start with a building shell that accommodates your process and meets planning needs, you can save nine-plus months in construction.” 

Facility refurbishment and renovations represent more than 60% of Fluor’s work, adds Dave Watrous, vice-president, advanced technologies and life sciences, Fluor Corporation. Reconfiguring existing life-sciences manufacturing space or using suitable vacant buildings for a box-in-a-box approach can both accelerate speed to market.

ATMP capacity crunch

Speed is crucial in biologics manufacturing, especially in the fast-growing cell therapy and gene therapy industry as products are reaching clinical phase and there is a lack of manufacturing capacity. 

“For manufacturing these advanced therapies, CDMOs [contract development and manufacturing organizations], can be scheduling six to 18 months out, and this wait time is disruptive to a company’s go-to-market strategy,” says Joe Makowiecki, Enterprise Solutions director of business development at GE Healthcare Life Sciences. He says that despite CDMOs adding capacity, many cell and gene therapy companies are deciding to build their own capacity using modular, box-in-box facilities that can be delivered in a year or less.  

“In many cases, having a facility up-and-running and licensed may be the critical path to gaining approval for a new product. As such, site startup timing is critical,” says Mitch Lower, vice-president of global engineering for AveXis, a Novartis company specializing in gene therapies. The company received an honorable mention in the 2019 International Society for Pharmaceutical Engineering (ISPE) Facility of the Year Awards (FOYA) for being one of the first companies to scale up a gene-therapy manufacturing process and doing so on a short timeline. To build its Libertyville site near Chicago, IL, AveXis used G-CON Manufacturing’s prefabricated cleanroom PODS-built off-site in parallel with facility construction-which expedited startup.  

AveXis also purchased and refurbished a facility in Longmont, CO in 2019 to add manufacturing capacity. The facility is operational and is undergoing the remaining steps to become licensed, which the company expects to occur in 2021. A facility the company is building in North Carolina is also anticipated to become licensed in 2021.

“There are benefits and challenges to both purchasing an existing facility and building a new facility,” says Lower. “Purchasing an existing facility may be more cost effective and have an expedited startup schedule. However, the existing infrastructure and facility layout may drive additional costs to retrofit to accommodate the necessary manufacturing process. When building a completely new facility, the timeline may be longer; however, you will have the flexibility to build the facility to meet the needs of your unique and novel manufacturing processes.”  

Although AveXis is today mainly using manual processes, it is moving towards automation in its existing and new equipment and facilities, says Lower. 

The lack of automation that is currently common in the novel ATMP industry is changing, agrees Noel Maestre, Life Science Core team leader at CRB. “These novel therapies are quickly proving a need for process closure and automation, which in turn is driving equipment vendors to create and test novel equipment solutions,” notes Maestre. 

Some equipment vendors are employing adaptable and flexible “plug-and-play” automation platforms. “Customers want options around automation,” says Makowiecki. “Some may prefer to start small with entry-level automation, but we aim to make flexible and scalable automation platforms that can grow and scale to more centralized and advanced levels.”

OSD trends

In OSD manufacturing, facility layout is becoming more important as equipment and processes are moving toward greater integration, says DiProspero. Continuous manufacturing and processes such as direct compression, which are growing in use, are examples of integrated systems, but integrating unit operations is also preferred in more traditional OSD processes. “A typical integrated equipment train will incorporate material handling, high shear granulation, wet milling, fluid bed drying, dry milling, and granulation collection in a linked, semi-continuous contained operation,” explains DiProspero. Efficient product flow is crucial. “Good facility design is marked by uninterrupted uni-flow process direction, with appropriate hold and work-in-progress spaces and minimization of cross/backflow. Specifically, modern washing operations make use of a dirty-wash-clean uni-flow arrangement for improved efficiency and compliance.”

Modular and prefabricated construction is being used in OSD manufacturing. “This type of construction is well suited for powder processing operations due to good cleanability, visual aesthetics, and the ability for use of glass to bring light into the spaces and provide for a user/operator-friendly working environment,” says DiProspero. 

Modular approaches

Modular approaches are transforming the way the industry builds facilities. Both modular design methods using standardized templates and modular construction methods for buildings and systems can improve speed to market, says a report by the BioPhorum Group (4).

Modular construction includes factory fabricated utility skids, wall panels, or entire rooms or building sections, which can save time and improve quality and construction safety, explains Bohn. He points out that, although the initial cost of modular construction is typically more than that of field-built alternatives, the savings that comes from a shortened timeline is quantifiable. Factory testing reduces problems in the field and makes commissioning, validation, and start-up faster. 

G-CON’s PODs, for example, are prefabricated, autonomous, plug-and-play cleanroom environments, which can be installed within an existing facility or as part of new greenfield construction, for any type of bio/pharma manufacturing, including OSD, aseptic filling, and cell and gene therapy, says Dennis Powers, vice-president of business development and sales engineering at G-CON. The mobile facilities provide flexibility because they can be transported anywhere to quickly add or subtract capacity. 

Modular construction started out in the bio/pharma industry for building infrastructure in developing countries with a lack of skilled construction capabilities, but now speed is the primary driver. “Modular construction and prefab cleanrooms are often must-have components in any new facility. Even in very mature market locations, these strategies help simplify and accelerate the market delivery strategy for most products,” adds Watrous. 

“The modular facility concept is a paradigm shift that provides companies with options for establishing rapid and flexible in-house production,” says Makowiecki. “With standardized, modular systems, typically 80% of the design work has been completed, which reduces design time and results in faster speed to delivery,” explains Makowiecki. 

GE Healthcare’s FlexFactory is a modular end-to-end biomanufacturing platform, and the company reports that it has sold close to 70 FlexFactories globally to date. Four of these FlexFactories were installed inside of the company’s KUbio facility, which is the FlexFactory inside of a modular, prefabricated facility. Pfizer’s Biotechnology Center located in Hangzhou, China, for example, is a KUBio facility, and it won an ISPE FOYA 2019 award for project execution.

In 2019, GE Healthcare launched the KUBio Box for viral-vector-based gene therapy manufacturing; in this box-in-box approach, the FlexFactory platform in a modular cleanroom facility is intended to be placed inside a new or repurposed space or shell-building. The KUBio box for viral vectors is a cGMP, biosafety level 2 modular facility solution. 

“We’re also having discussions around building biomanufacturing campuses and shell facilities to house the modular boxes. A best practice approach here is to build for what you need today but allow for enough space in your facility or facility shell to expand,” explains Makowiecki. He expects the KUBio box offering will expand into additional product modalities and biomanufacturing scales. 

Standardizing for speed and quality

Standardization of facility modules, equipment, unit operations, automation, and consumables are essential to the speed of deploying modular facilities and efficient and effective technical transfer. These capabilities support the trend to distributed manufacturing, with the same company manufacturing a drug in multiple regions rather than one centralized location, notes Makowiecki.

“Standardized, closed systems provide optimal aseptic processes that support very high drug product quality,” adds Chris Procyshyn, CEO and co-founder of Vanrx Pharmasystems. He notes that other industries rely on standardization for reliability and safety, and he says that the pharma industry needs to move to this model. “If the process from one site can be repeated on the same machine at another site, that’s a positive change in our industry,” suggests Procyshyn. Vanrx designs closed robotic workcells with “purpose-built robotics and a standard method of handling all types of containers to achieve repeatability,” he explains. These systems remove human involvement to make the aseptic process more robust, which benefits drug quality. 

Standardized equipment improves speed to market. For example, WuXi Biologics moved from purchase order of the Vanrx workcell to their first GMP batch release in only 15 months, says Procyshyn. 

Placing standardized filling machines inside a modular cleanroom further increases speed and gives companies the ability to implement a fully prequalified facility within months, says Procyshyn. 

The Microcell POD is an integrated solution from Vanrx and G-CON that meets the “increasing industry need for rapidly deployable turnkey aseptic filling capability for small batch therapies, specifically in the cell and gene therapy space,” adds Powers. Standardization lends itself to “scaling out” rather than “scaling up.” The standard POD design can be replicated to rapidly increase manufacturing capacity, he notes. 

Collaborating on integration is key

Although standardizing improves quality and speed, integration of the equipment into the facility building is still important. For example, in building the Bayer facility in California in 2019 using GE’s FlexFactory, Fluor’s team helped design the optimal people, product, and material flows around the established FlexFactory set-up, and then integrated these flows in the building envelope and associated utilities and infrastructure. This collaborative process with an integrated end result reflects the future of the industry, says Watrous.

References

1. PharmTech, “GSK Completes Retrofit of Maryland Facility,” PharmTech.com, Oct. 4, 2019.
2. GSK, “GSK Invests $120 Million in Next-Generation US Biopharmaceutical Manufacturing Facility,” Press Release, Sept. 25, 2019.
3. The Discovery Labs, “The Center for Breakthrough Medicines is Building the World’s Largest Cell and Gene Therapy Contract Development and Manufacturing Organization (CDMO) to Launch in King of Prussia, PA,” Press Release, Jan. 23, 2020.
4. BioPhorum Group, “Improving the Biomanufacturing Facility Lifecycle using a Standardized, Modular Design, and Construction Approach,” White Paper, June 2019. 

Article Details

Pharmaceutical Technology
Vol. 44, No. 4

April 2020
Pages: 16–21

Citation

When referring to this article, please cite it as J. Markarian, “Building Better Manufacturing Facilities," Pharmaceutical Technology 44 (4) 2020.