There are three basic equipment components that may comprise in-line dilution equipment. These include piping, fluid flow, and mixing devices. A variety of pump types may be used. Mixing devices may be either static mixers or dynamic blending modules. The materials of construction of the aforementioned equipment components will also be discussed. There are two types of control instrumentation used in conjunction with the above: these are mass flow meters and analytical instruments such as pH and conductivity measurement devices. A programmable logic controller (PLC) integrates the operation and control of all of the above.
Piping
Piping is fundamental to all equipment designs. Like most equipment in the biopharmaceutical industry, in-line dilution skids are primarily constructed of 316L stainless steel tubing connected by sanitary fittings and EPDM or silicone gaskets. EPDM (ethylene propylene diene monomer) and silicone are widely used in the pharmaceutical industry due to 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 liquids it will contact and must have USP Class VI testing. Other metals such as Hastelloy or AL6XN can be substituted for 316L Stainless Steel in areas where corrosive products are handled; these other metals have different ratios of elements and therefore have different properties. The product concentrates may require special consideration, but once diluted the standard materials could be acceptable.
Fluid Flow
- Compressed Air. In pressure flow designs, fluid flow is accomplished by using a 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 to no pressure.
- 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 and be trapped between the lobes and the interior shell of the pump. The liquid moves along the outside of the lobes, not through the middle where the two lobes mesh. The liquid is then forced through the outlet at a greater pressure than the inlet side, which results in flow.
- Diaphragm metering pumps. Diaphragm metering pumps are also utilized in metering and blending module designs. Metering pumps move precise volumes of liquid per revolution to provide accurate flow rates. This class of pumps moves liquids in two stages: the suction stroke and the discharge stroke. During the suction stroke, liquid is pulled into the pump cavity past the inlet check valve. During the discharge stroke, the inlet valve closes; the outlet valve opens, and the liquid is pushed out. The amount of flow is changed by either changing the stroke length or by adjusting the cycle frequency.
- Centrifugal pumps. Centrifugal pumps may also be utilized in some skid designs to generate fluid flow. A centrifugal pump utilizes 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, which results in flow.
Mixing devices
- Static mixer. Static mixer is a piece of pipe with baffling inside to force a turbulent condition. The turbulence causes the liquid to mix.
- 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.
Control Instrumentation
- Mass Flow Meters. These meters measure the mass flow of a liquid in units of weight per time, for example kilograms/second. A mass flow meter uses scientific phenomena known as the Coriolis Effect to measure the changes in vibration of a pipe as mass flows through it. Because the flow is calculated using vibration, the piping through the instrument is continuous and there are no moving parts. The result is a very reliable instrument that does not wear out and does not drift out of calibration. Below is an example of a straight tube mass flow meter. The blue component is the transmitter that interprets the signal from the meter and sends it to the skid computer.
- Conductivity Sensors. Conductivity is a measurement of the ability of a solution to conduct an electric current. The instrument measures conductivity by placing two plates of conductive material with know area and distance apart in a sample. Then a voltage potential is applied and the resulting current is measured. Conductivity is impacted by the amount and type of chemicals in the solution that are able to conduct electricity, such as metals and salts. Conductivity is also impacted by solution temperature; therefore, adjustments must be made to compensate for this effect. Instruments usually perform this automatically.
- pH Sensors. pH is a measure of acidity or alkalinity. The amount of hydrogen ions (H+) causes a liquid to be acidic (high concentration of H+) or alkaline (low concentration of H+). The pH range is measured from 0-14. A pH sensor contains a special glass bulb that detects the hydrogen ions and creates a millivoltage (mV). The glass bulb is filled with a solution that passes the voltage to a wire, which can then be converted to the pH reading. Like conductivity, pH sensors are also impacted by temperature. Some sensors can automatically measure and compensate for temperature. Caution must be taken for product solutions that are at the extremes of the pH scale (0 or 14) because some sensors cannot measure at these ranges and can be damaged by these harsh solutions, referred to as “pH poisoning”.
- Optical Sensors. Optical sensors include UV-Absorption and NIR (Near Infrared). This family of sensors utilizes light to determine the chemical composition of the solution. Light is passed through the solution to a detector on the other side. The instruments are then able to relay the information back to the computer for evaluation.
- Parametric Parameters. This is a general term for the measureable properties of the process stream that are one step removed from the parameters that are directly controlled by the equipment. An example of a control parameter is the mass flow rate or volumetric flow rate of the streams. These parameters are directly related to the pumping of the fluids. Examples of parametric parameters are the conductivity or pH of the outlet stream. These parameters must be measured in order to use them for feed back control of the inlet stream.
- Programmable Logic Controller (PLC). The PLC is a computer that contains a specific list of instructions for the equipment to follow. The PLC is the brains of the equipment that ties everything together. The instructions are known as the program or code. The program is written to execute the process and generate a final product that meets the user requirements or product specifications. The program tells each component what to do, when to do it, and for how long. It also collects all of the information from the sensors on the skid and uses the data to determine if the process is operating within the acceptable limits. If not, it will attempt to correct the process to maintain it within the acceptable limits. The program also contains to alert the operator of unsafe or out of specification conditions and may stop the process completely if the equipment is not able to correct the problem.
