Control instrumentation monitors the control parameters for solution input to the system, and monitors parameters measuring
the attributes of the diluted solution. The following are used:
Mass flow meters. A mass flow meter uses the Coriolis effect to measure the changes in vibration of a pipe as mass flows through it. Because
there are no moving parts, this results in a reliable instrument that does not wear out and is not likely to drift out of
calibration (Figure 8).
Conductivity sensors. Conductivity is impacted by the amount and type of ionic chemicals such as metals and salts in the solution. It is also impacted
by solution temperature; therefore, adjustments must be made to compensate for this effect (Figure 9).
pH sensors. pH is affected by temperature, but 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, which is referred to as "pH poisoning," Figure 10).
Photometric sensors. Photometric sensors include UV and NIR spectrometers. This family of sensors uses specific wavelength light to determine
the chemical composition of the solution. The instrument passes light through the solution to a detector on the other side,
and then relays the information back to the computer for evaluation.
Programmable Logic Controller (PLC)
The PLC is a computer that contains a specific list of instructions, known as the program or code, for the equipment to follow. It also collects all of the information from the sensors on the skid and uses the data to determine
if the process is operating in the acceptable limits. If not, it will attempt to correct the process to maintain it in the
acceptable limits. The program alerts 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.
The process materials are mixed to prepare the final diluted solution of interest, as described in the following:
Process solution concentrate. In many cases, concentrates can be purchased or prepared in concentrations of 10x or more. Concentrates can be supplied in
disposable flexible bags or be prepared in existing solution preparation vessels.
Diluting agent or diluent. Water is the most common diluent. The specific grade of water required depends on the specifications of the final product.
Other diluting agents such as isopropyl alcohol are also possible, which must be evaluated for material compatibility and
The dilution skids can operate continuously for long periods of time and remain extremely reliable. The processes are usually
designed with a number of precautionary measures to keep the equipment running. For example, redundant measurements can be
used for pH and conductivity. This means that there are two sensors for each measurement. In the event that the primary sensor
drifts out of tolerance or fails, the secondary sensor takes over and sounds an alarm to alert the operator of the event.
Alarms are the second precautionary measure. Since the skids are automated, the operator does not need to attend to the process
at all times. The alarms communicate any unusual conditions through messages on the screen, audible horns, or even through
plant monitoring systems.
Post-validation and qualification maintenance and monitoring are important to ensure reliable operation of the equipment.
The following items should be considered:
Preventive maintenance. The equipment supplier for each of the components should provide recommended maintenance procedures and the appropriate
intervals to perform each procedure in order to maintain optimal working condition.
Calibration. The factors involved in determining the calibration frequency can include: critical versus non-critical measurements, the
number of batches produced between calibrations, and the calibration history of the instrument.
Cleaning. The cleaning of an in-line dilution skid is accomplished by automated clean-in-place (CIP) procedures, which are much preferable
to those of a traditional process involving human interaction that introduces error and subjectivity into the process. Automated
processes are highly repeatable and reliable when designed and validated correctly. This again reinforces the concept of QbD.
Steam sanitization and sterilization. All components and piping must be designed properly to eliminate crevices and ensure steam will contact all surfaces. All
components must also be compatible with the high temperatures of a steaming process (typically 121 °C). Any moving parts,
such as pumps, must be designed with sufficient clearances to allow for the expansion of the metal as the parts increase in