ENGINEERING CONSIDERATONS FOR IN-LINE DILUTION
Equipment for automated in-line dilution accomplishes the following process steps: concentrated solution is combined with
diluent solution, the combined liquids are mixed, solution concentrations may be adjusted depending on the system components,
and the final desired solution is delivered for its intended use. Engineering considerations needed to successfully accomplish
these steps are discussed in the following sections.
Equipment Design
There are two fundamental equipment designs for in-line dilution processes. Several variations of the basic designs are commercially
available. These variations differ primarily in the method used to generate fluid flow and measure the streams. Examples of
equipment designs include:
Figure 4
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Pressure-controlled. Fluid flow is controlled by changing the pressure of the inlet streams. For example, a beverage machine uses pressurized
carbon dioxide (CO2) to mix concentrated syrup with water to produce soda with the appropriate ratio of syrup to water (Figure 4).
Mass-controlled. Fluid flow is controlled by measuring the mass flow rate.
Volumetric. Fluid flow is controlled by precision metering pumps.
Parametric parameter feedback. Feedback control is accomplished by measuring the output of selected solution attributes.
Parametric parameter feedback with dynamic blending. Feedback control is accomplished by measuring the output of select solution attributes and blending is performed in a continuously
mixed blending module.
Designs such as pressure-controlled, mass-controlled, or other mechanically based controls are not considered QbD or PAT because
they do not directly identify, monitor, and control a critical process parameter (CPP). The CPP in buffer blending, for example,
is the chemical make-up of the buffer (molarity and pH), not its mass, pressure, or volume. By controlling the CPP, one can
eliminate the impact of out-of-specification (OOS) concentrates and the extreme difficulty and cost of trying to make nearly
perfect concentrates with mass, pressure, or volume blending designs. Designs that use a blending module with PAT and feedback
controls make it possible for the dilution process to decouple the variability of the final product from the variability of
the concentrate.4
Equipment Components
There are three basic equipment components that comprise in-line dilution equipment. These include piping, fluid flow devices,
and mixing devices. Control instrumentation includes mass flow meters and analytical instruments such as pH, conductivity,
or near-infrared (NIR) instrumentation. A programmable logic controller (PLC) integrates the operation and control of all
components.
Piping and Material Compatibility
Like most equipment in the biopharmaceutical industry, in-line dilution skids are primarily constructed of 316 L stainless
steel tubing connected by sanitary fittings and ethylene propylene diene monomer (EPDM) or silicone gaskets. EPDM and silicone
are widely used in the pharmaceutical industry because of their favorable chemical and temperature resistance and spongy-elastic
properties. Gaskets are also available in Viton, PTFE, and many other compounds. The material chosen must be compatible with
the process liquids and must pass US Pharmacopeia (USP) Class VI testing. Other metals such as Hastelloy or AL6XN can be substituted
for 316 L stainless steel in applications where corrosive liquids are handled; these alternate metals have different elemental
ratios and different compatibility properties. Product concentrates may require special considerations for compatibility;
after dilution, standard product contact materials should be acceptable.
Fluid Flow Devices
Fluid flow is accomplished by the following:
Compressed air. In pressure flow designs, fluid flow is accomplished by using compressed gas to pressurize the initial source of the concentrate
and diluent. Since fluids flow from high to low pressure, the fluids under pressure have the ability to flow through the process
because the outlet of the process has little or no pressure.
Figure 5
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Positive displacement rotary lobe pumps. In mass-flow or blending module designs, rotary lobe pumps can be used. Rotary lobe pumps consist of two rotating lobes that
are similar to gears. The inlet side of the pump allows liquid to flow in. The liquid is then forced through the outlet at
a greater pressure than the inlet side, which results in flow (Figure 5).
Diaphragm metering pumps. Diaphragm metering pumps may be used in metering and blending module designs. Metering pumps move precise volumes of liquid
per revolution to provide accurate flow rates. The amount of flow is changed by either changing the stroke length or by adjusting
the cycle frequency.
Figure 6
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Centrifugal pumps. A centrifugal pump uses an impeller to draw in liquid at the center and force the liquid outward as it spins. The liquid gains
energy (increased speed) as it is forced outward by the impeller. As the liquid exits the pump it slows down again, but now
contains energy in the form of increased pressure, resulting in flow (Figure 6).
Mixing Devices
Mixing devices include:
Static mixer. Static mixers are pipes with baffling inside to force a turbulent fluid flow condition. The turbulence causes the liquid
to mix.
Figure 7
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Blending module. A blending module is a small continuous mixing chamber that is located between the inlet and outlet streams. The chamber
could consist of a small tank or a large pipe (Figure 7).
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