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.
Addressing powder flow concerns
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).
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.
Figure 2. An asymmetric container design allows optimal mass flow behavior of both coarse and fine powders.
Controlling discharge rate
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.
Figure 3. 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.
1. BioPlan Associates, 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,
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