Growing interest in continuous drug manufacturing has brought greater attention to in-line blending, a process that the petroleum and fine-chemicals industries have used for decades. In-line blending entails feeding ingredients continuously into a mixer that generates a homogenous blend without interruption. The blender is meant to run for extended periods, but it typically contains only a small amount of material at a time. Like other continuous processes, in-line blending promises to yield products of consistent quality, increase efficiency, and reduce the manufacturer’s costs.
The pharmaceutical industry has used in-line blending to add powders to liquid formulations for five to 10 years, says Matt Chapas, manager of manufacturing science and technology at Ben Venue Laboratories. But the process also can blend liquids together quickly and easily, and it could potentially be used to manufacture a global vaccine continuously. In addition, companies are showing increased interest in using in-line blending to mix free-flowing powders continuously, although not many drugmakers have used the process for this application.
One advantage of in-line blending is that it relies on simple equipment and does not require tanks or agitators. Static mixers (tubular devices with no moving parts) contain mixing elements that promote radial dispersion as materials flow around them. Manufacturers can set up an in-line blending operation by installing static mixers in a pipeline. Valves, flow meters, positive-displacement pumps, and metering pumps are all necessary to control the flow of material accurately. In many cases, a drugmaker can use its existing equipment for the process, says Art Etchells, an independent consultant and DuPont fellow emeritus.
Some manufacturers have realized that in-line blending can greatly increase the wetting of powders and enable enhanced and consistent solubilization. When operators manually introduce powders that are difficult to dissolve into liquid formulations, the powders sometimes pool on the surface. “In-line blending could potentially resolve these issues without extending mixing times or requiring the addition of nonaqueous solvents,” says Chapas.
The process also can help provide the containment needed to work with cytotoxic drugs. In-line blending limits potential exposure to the active in a powder state to the material-loading step. Ben Venue worked with a leading supplier to design disposable isolators that operators use when loading the in-line blending hopper, thus reducing the potential for operator exposure to highly potent actives.
Perhaps the biggest advantage of in-line blending is that it lets operators control the rate of ingredient addition consistently, thus allowing great control of the blending process. The approach “could result in more consistent and reproducible blending processes, as well as an optimized process from an efficiency standpoint,” says Chapas.
Although in-line blending is best suited to continuous operations that produce large volumes of drug, companies could use the technique for batch processes, too. For example, operators may want to add a hydrophobic powder such as magnesium stearate to a suspension as it is being milled. Dumping the powder into the liquid usually produces an undesirable mixture of powder, air, and liquid. “The way to break those bubbles containing powder is to apply shear,” says Fernando J. Muzzio, member of Pharmaceutical Technology’s editorial advisory board and director of the National Science Foundation’s Engineering Research Center on Structured Organic Particulate Systems at Rutgers University. “One way to do it effectively is to use an in-line mixer that provides that shear to induct the powder gradually, force wetting, and displace the air. That is an application done in batch. We have built tanks like that for pharmaceutical companies to help them solve those kinds of problems,” says Muzzio.
Several companies also have decided that it makes sense to mix continuously when the mixture will be roller compacted, even in a batch system. If operators have to lubricate product after it comes out of the roller compactor and before it reaches the tablet press, “it’s natural then to say, ‘All right, we can use an in-line mixer, we can add the magnesium stearate, and we can go straight into the tablet press and save a lot of headaches,’” says Muzzio.
In-line blending can accommodate process analytical technology to help deepen understanding and enhance control of manufacturing operations. The method can thus please regulators and drugmakers alike. Considering in-line blending’s other advantages and its applicability to continuous and batch processes, increased attention to the technique could well widen its popularity within the pharmaceutical industry.