The biopharmaceutical industry is seeing a trend to smaller-volume production for manufacturing products such as vaccines, biotherapeutics, biosimilars, and antibodies. The new generation of molecules has higher potency and improved productivity compared to legacy molecules, which reduce batch sizes. In addition, these products have frequently-changed formulations and smaller markets that require short production campaigns and more frequent turnarounds than traditional products. “Manufacturers today are interested in ‘in market, for market’—producing locally with much smaller batches of 1000 to 2000 L on average,” says Parrish Galliher, chief technology officer at Xcellerex. In response, industry is beginning to embrace flexible manufacturing systems, which address the growing need for short campaigns by offering lower capital costs and reduced time to production compared to traditional manufacturing.
The flexible manufacturing revolution began with single-use bioreactor technology, says Galliher. While conventional manufacturing systems require extensive cleaning and validation between product changes, single-use systems are simply disposed of and replaced with a clean, presterilized system, which makes the process much more flexible. Modular factory concepts take this flexibility another step by creating prefabricated, interchangeable workspaces or process modules that can be more quickly installed with lower capital costs than needed to build a conventional facility.
New, mid-tier biotechnology companies have been early adopters of flexible manufacturing because they do not have a lot of legacy equipment, says Galliher. Although the conservative pharma industry is usually slow to adopt new concepts, Galliher notes that regulators are supportive of flexible manufacturing, which can offer higher quality manufacturing and reduced risk, and confidence is building as facilities receive approvals.
Facility of the Year Award
One example of a facility that embraced flexible manufacturing is Rentschler Biotechnologie’s contract manufacturing plant in Laupheim, Germany. Rentschler recently earned the International Society of Pharmaceutical Engineers (ISPE) 2012 Facility of the Year Award (FOYA) for Equipment Innovation for its REX III manufacturing facility that uses a flexible-manufacturing design. The new, 9800-ft2 facility uses single-use technology and multipurpose, cleanroom suites for an annual capacity of up to 10 manufacturing projects with up to 24, 1000-L batches. “This design meets our need for flexibility, allowing us to more efficiently run fewer batches of multiple products for either commercial production or development and clinical trials,” says Klaus Schoepe, senior vice-president of client relations at Rentschler Biotechnologie. He says that Rentschler looked carefully at the off-the-shelf disposables and worked with suppliers to create customized, pre-assembled, single-use kits that optimize process economy and safety. Modular cleanrooms add flexibility and allow the company to easily set up production equipment according to customer’s requirements.
Two types of self-contained modules—room-sized or unit operation-sized—are currently available for flexible biopharmaceutical manufacturing.
One approach to modular construction is a self-contained modular cleanroom. For example, G-Con’s “pod”, or Mobile Biotherapeutic Manufacturing Facility Unit (MBFU) is designed to be docked to a clean corridor within standard building “gray space”. Pods can be added to an existing process train and can later be re-arranged within the gray space. One of G-Con’s standard MBFUs measures 18 x 42 ft with a 13-ft height and includes a process area, mechanical area, and gowning area. Pods enable fast construction at a fraction of the cost of traditional builds, according to G-Con. A 145,000-ft2 plant-based vaccine facility was built in 18 months, from conception to production, by building G-Con Pods and the host facility simultaneously. G-Con partnered with Rockwell Automation to enable “plug-and-play” capabilities between the process equipment, pod, and facility. G-Con recently announced a global partnership with Sartorius-Stedim Biotech, which will be selling its own version of the pods under the brand name FlexMoSys.
Xcellerex’s compact modular manufacturing system shrinks the cleanroom down around the unit operation. The Xcellerex FlexFactory, introduced to the market in 2009, encompasses the entire production train, from cell culture to bulk product, and segregates each unit operation into individual clean room modules just big enough to hold the operation. Each module has an individual heating, ventilation, and air-conditioning (HVAC) system that provides positive-pressure, single-pass, fresh air, thus completely separating each module from those around it. These modules are laid out in an open ballroom suite, in which the operators are no longer inside the cleanroom, but can move up and down the entire line, accessing the operation inside the cleanroom modules without changing gowns. Galliher says the Xcellerex design can cut capital investment in half compared to traditional facilities, primarily by eliminating the infrastructure needed to clean and sterilize, eliminating gowning rooms and corridors, and reducing purification clean-air requirements by 80–90%. He adds that modular systems and parallel build-out and validation can reduce time to GMP production to 12–15 months from 3–5 years for traditional manufacturing. Other advantages are reduced operating expenses, lower labor and gowning requirements, a 35% smaller space needed for the plant, lower investment risk, and greater flexibility in manufacturing.
Because each module in the FlexFactory is self-contained, different drugs can even be processed by the same manufacturing team in the same line or parallel lines in the same suite, one behind the other. “Simultaneous multidrug production is the next frontier in manufacturing efficiency, cost-of-goods-sold reduction, and asset utilization,” says Galliher.