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.


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-ft

 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-ft

 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.

Articles

Production Lines

Modular factory concepts, which take flexible manufacturing to the next level, are beginning to take hold in the biopharmaceutical industry.

Modular Factory Concept Gains Traction

 Single-use powder mixing and delivery system now available in 1000-L size


 EMD Millipore, the life-science division of Merck KGaA, added a larger, 1000-L system to its line of Mobius mixers, which already includes 100-, 200-, and 500-L sizes. The systems use integrated, single-use, powder delivery, mixing, and filtration technology, which gives biopharmaceutical manufacturers increased operational flexibility and decreases process and validation time and contamination risk.

“We are seeing an increased number of new applications for single-use technologies. It is now common to see single-use mixing systems and storage systems in pilot and production scale. With the introduction of the Mobius 1000-L single-use mixer, we are providing our customers with a wider range of volumes for increased flexibility to meet their specific processing needs,” say senior applications engineer Sue Walker and product development engineer John Saragosa of EMD Millipore.

 Automated milling system provides an advanced processing solution for jet milling of powders

Containment-unit supplier Powder Systems Ltd (PSL) collaborated with the suppliers of the ARTMiS Automated RealTime Milling System to provide a secure, isolated milling suite. The ARTMiS system, introduced last year, combines Sturtevant’s Micronizer Jet Mill, Malvern’s Insitec particle-size analyzer, and Schenck’s AccuRate PureFeed feeder in a fully automated system that simplifies and optimizes the jet-milling process. For high-potency or high-value materials that need containment of the jet-milling process, the PSL isolator provides containment to nanogram levels. The isolator was designed for enhanced operator viewing using an L-shaped window. The glove ports and cabinet-depth were designed ergonomically so that all parts of the isolator can be reached without stretching, says Stuart Evans, product engineer at PSL. An assured explosion protection system is integrated into the design. PSL offers an optional nitrogen purge system that is able to achieve less than 1% relative humidity.

PharmTech's monthly newsletter, Equipment and Processing Report, reviews the Editor's Picks for the March 2012 edition from EMD Millipore, ARTMiS, and Powder Systems.

March 2012 Editor's Picks: Products from EMD Millipore and Powder Systems

Increased availability has accelerated the use of single-use systems in the biopharmaceutical industry. Membrane adsorbers, bioreactors, and mixing systems are currently experiencing the fastest growth of all single-use systems (1). Single-use mixing systems are designed to efficiently mix media and buffer solutions and to produce bulk drug substances and vaccines. Single-use mixers can increase operational flexibility, decrease process and validation time, and decrease risk of contamination compared with traditional mixing systems, according to EMD Millipore’s research.

Mixing media and buffer solutions is a critical task in the biopharmaceutical industry. The use of concentrates, which have a high percentage of solids in the mixture, is expected to become more prevalent. As a result, powder delivery and mixing systems must be able to handle higher solids loading. In addition, powder delivery and mixing systems must be able to efficiently handle and properly dispense a wide range of solids from fine to coarse powders. A solid’s particle size, type, and physical properties (i.e., moisture content, electrostatic charges) will all impact how the solid flows. For example, a small particle may be electrostatically charged so it will not flow as easily as a larger, uncharged particle. Without the proper equipment, powders can be challenging to handle when balancing dosing accuracy with operational speed and rapid turnaround of the equipment from one batch or product to another. A powder container should be able to handle and to dispense solids at a consistent, controlled rate and be easily washed to remove residual powder.


 An optimal powder-delivery container design prevents residual powder from accumulating at any point in the container. The container geometry significantly affects the flow rate of bulk solids. There are at least three possible flow issues that result from improper container geometry. The first is ratholing, which occurs when powder only flows through a channel above the opening, but leaves powder at the sidewalls (see Figure 1). Ratholing is more likely in containers with shallow angles and when using powders with strong cohesive forces because material would be more likely to remain stagnant outside the channel. The second potential issue is arching, which occurs when powder bridges across the outlet and stops flow (see Figure 1). Arching may result because of particle bonding in which the particle size is relatively large compared with the outlet diameter. The final potential issue is erratic flow, in which flow alternates between ratholing and arching (see Figure 1).

 Potential issues with powder flow from containers due to improper design include ratholing, arching, or erratic flow. All figures are courtesy of the authors.

Studies on powder properties conducted in Millipore’s laboratory compared symmetric container designs with a patented, asymmetric design (Mobius powder-delivery system, EMD Millipore). An asymmetric geometry, shown in Figure 2, optimizes flow performance of solids, eliminates potential bridging at the discharge outlet, and minimizes dead areas. The asymmetric design eliminates the uniform symmetry of forces that creates arching and encourages mass flow of both coarse and fine powders. Permeability tests defined the limiting rate of discharge that would prevent arching and erratic flow. 

. An asymmetric container design allows optimal mass flow behavior of both coarse and fine powders.


 Controlling the rate of discharge into the mixer is important. Some current designs require the user to clamp or tie the end of the container to the mixer, which prevents a controlled discharge rate. Alternatively, a molded butterfly valve with an actuating flap allows the user to manually control powder flow rate from the container into the mixer (see Figure 3, Mobius powder delivery system, EMD Millipore). The valve contains a swing-out handle that permits compact storage. A screw cap fits over the entire valve to protect the outlet and the handle during transportation and long-term storage.

. Contact surface of valve (A) and exterior of valve in closed position (B).


 After dispensing the powder into the mix vessel, the container is washed to make sure all materials have been removed from the bag. Containers with a single side port do not allow complete powder removal in a wash-down because the wash cannot completely cover the interior of the container. A wash-down design with a handle that supports the container and evenly distributes a stream of water to remove powder from the sidewall improves cleaning. A film bladder inside the container, at the top, sprays an angled pattern of water that permits rinsing of the upper and lower surfaces (Mobius powder-delivery system, EMD Millipore). 

As single-use system options continue to be introduced into biomanufacturing operations, powder delivery and mixing systems must keep pace in order to support faster, more flexible processes.

8th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production

 (Rockville, MD) Preliminary Data, Feb. 2011, Publication Date Apr. 2011.

Sue Walker is senior applications engineer at the Biomanufacturing Sciences Network of EMD Millipore and John Saragosa is product development engineer at EMD Millipore, 

900 Middlesex Turnpike, Billerica, MA, USA 01821, tel: 781.533.5963, 

In the Mixer

Powder-container design affects discharge rate, cleanability, and powder flow. Flow problems, such as ratholing, arching, and erratic flow, can be eliminated with appropriate container geometry.

Container Design Meets Powder Handling Needs for Single-Use Mixing Systems

Q. In our tablet-coating process, we are losing up to 15% of our coating solution in each processing run. What can we do to prevent this problem in order to reduce waste and increase our cost efficiency?

A. Wasted coating material is an industrywide issue for companies using standard (conventional) tablet coaters, with the average coating loss between 10 and 15%. The only way to reduce loss in conventional coaters is to slow down the spray rate and airflow. This will improve efficiencies but lengthen the coating process. Although it comes at a significant capital cost, the most forward-thinking way to solve this problem now and in the future is to investigate the benefits of installing a high-efficiency tablet coater. These advanced coaters offer a variety of features that can streamline your processing.

For example, the size and shape of coating pans plays an important role in efficiency. Traditional coating pans are short in length and large in diameter, which creates a thick tablet bed when solids are put in the coater. Thicker tablet beds have a zone in the middle that is slow moving, and tablets in this area do not get exposed to the surface of the bed as often. The result is a longer coating process that uses more coating solution and wastes energy.

On the other hand, high-efficiency coaters have coating pans that are longer in length but smaller in diameter, which allows the tablet bed to be spread wider and eliminates the slow-moving zone. When tablets are in constant motion, they enter the spray zone more often. This leads to faster coating times, as well as less wasted coating materials. As an added bonus, tablets are coated more uniformly in this type of pan.

Advanced tablet coaters also reduce waste by eliminating spray drying. Conventional coaters send airflow from the top or side of the coater, across the spray zone, through the tablet bed, and out. Bringing hot air into direct contact with spray while it is airborne, however, dries part or all of the coating solution before it hits the tablets. The result is wasted coating product. 

High-efficiency coaters are game changers because airflow enters from beneath the tablet bed and is distributed over the entire length of the pan. All airflow through the tablet bed is in the direction of flow, thereby leaving no hot air in the spray zone. High-efficiency coaters ensure droplets are wet when they hit the tablet surface, resulting in the use of less coating solution to achieve uniformity.

—Martin Hack, vice-president and general manager of L.B. Bohle.

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Troubleshooting

In our tablet coating process, we are losing up to 15% of our coating solution in each processing run. What can we do to prevent this problem in order to reduce waste and increase our cost efficiency?

Equipment and Processing Report-03-21-2012

Modular Factory Concept Gains Traction

March 2012 Editor's Picks: Products from EMD Millipore and Powder Systems

Container Design Meets Powder Handling Needs for Single-Use Mixing Systems

Reducing Waste in Tablet Coating