Automated In-Line Dilution | Equipment Components

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.

Data Monitoring - Instruments

This post discusses the instruments typically used for data logging.

Stand-Alone data loggers
A stand-alone instrument does not require a computer to operate and gather the data. A chart recorder is a common instrument included in this category. It uses a circular piece of paper and different pens to plot the measurements. The chart turns at a precise speed according to the programmed time period, such as a day or week.

Strip chart recorders are similar to circular chart recorders, with the exception that they print from a paper roll. As a result, much longer time durations can be charted before changing the paper.
Chart and strip recorders are limited in the number or data points that can be recorded simultaneously. Typically, there is a maximum of 4 pens available to plot the data.

Computer-Based Data Loggers
A Kaye Validator 2000 is a data logging instrument that can be used as a stand-alone or computer controlled data logger (i.e. tethered to a laptop computer). Up to 3 sensor input modules (SIMs) can be utilized and each SIMs can be configured with up to 12 sensors. Multiple units can also be linked together with an Ethernet cable. The Kaye Validator is 21CFR Part 11 compliant, and includes passwords, audit trails, and user levels. Data can be grouped to aid in calculations and graphing of the data. Data can also be exported to Excel for further analysis. Kymanox also has procedures available to make setup and operation easy for anyone (Kaye Validator SOP).

SmartReaders™ (http://www.acrsystem.com/) are ACR Systems data loggers that are available in many configurations. There are single channel and multi-channel data loggers as well as 8bit and 12bit models. 12bit models have an optional larger storage capacity and faster sampling rates of up to 25 points per second. Optional equipment is required to achieve this sampling rate. All data loggers utilize ACR System’s TrendReader software to configure the data loggers. The software is used to setup the data logger, view and graph the data, and export the data in various formats (including .csv files for Excel).

TempTale (http://www.sensitech.com/) data loggers are available in single and multi-use models. The data loggers are self-contained with internal sensors, memory, battery, and an LCD display. Storage capacity ranges from 1920 to 16,000 data points at sampling rates of 10 seconds to 2 hours. Data can be retrieved from the data logger directly to PDF format, which allows for easy access to the data from any computer. The TempTale Manager Desktop software is also available, and allows the user to view, save, print, graph, or export the data.

Veriteq Data Loggers (www.veriteq.com) are self-contained with internal sensors, memory, and battery. Storage capacity is 35,100 samples and sampling rates range from 10 seconds to once a day with the VL 2000 series. Configuration of the data logger is performed using the vLog software. The software is also used to perform calculations and to view, save, print, graph, compare, and export the data. The vLog software also provides audit trails and encrypted files which meet all the requirements of 21CFR Part 11 compliance.

Automated In-Line Dilution - Introduction

This blog will introduce the basic terms, engineering concepts, and quality concerns for automated in-line dilution equipment. An article with this content was also published in the Journal of GXP Compliance, an Institue of Validation Technology publication.

I welcome your comments as I hope to make this dicussion interactive with those of you familiar to this equipment or those of you who want to learn more.

Automated in-line dilution is an increasingly popular technology in the biopharmaceutical industry . In-line dilution is a process that can help solve some of the capacity, financial, and quality concerns that biopharmaceutical manufacturing plants may be facing with regards to process solution makeup and delivery. The information conveys a general knowledge about the technology, how it works, and what the quality impacts are.

It’s not uncommon for there to be some hesitation or uncertainty about implementing new technologies. After all, there is a comfort level with the current, traditional processes in which there are known failures and a general knowledge on how to address them. Implementing new manufacturing methods requires a familiarization period especially when people or organizations do not have a great understanding of what risks may be present and how to mitigate them. In addition to addressing new process methods, the quality & manufacturing science organizations have to consider the FDA guidance issued in 2004, PHARMACEUTICAL CGMPs FOR THE 21stCENTURY — A RISK-BASED APPROACH and ICH’s Q10 Among other things, these guidances urge companies to use process analytical technologies (PAT) to accomplish Quality by Design (QbD). The thought of incorporating PAT adds another level of complexity to adopting new process methodologies. To further complicate the issue, some people may already have negative feelings about PAT based on past experiences.

One of the many concerns in biopharmaceutical facilities is capacity. Biopharmaceutical companies are now obtaining much higher fermentation and cell culture yields than several years ago and have outgrown the capacity of downstream process equipment and production facilities. Biopharmaceutical companies are also challenged with manufacturing at large scales. Manufacturing 10,000L batches of process solutions in large tanks is inherently difficult. Making a 1 L solution in a lab can be done very precisely using analytical instruments that are calibrated to the milligram. A 1 L solution in the lab is also very easy to mix and does not take a long time to mix thoroughly. On the other hand, making a 10,000 L solution requires technology like load cells or level probes which have accuracies at least 10 times worse than the lab scales. If you add a bag a salt to a 10,000 L vessel, the mixing is anything but uniform and efficient; it requires significant time to achieve a uniform solution. Mixing is so difficult at large scale that mixing studies and validation are required to ensure the process is reliable and repeatable.

The scale up issue here is accuracy and ergonomics. If your development process was done using lab prepared solutions, you have to be prepared to deal with new variability once you scale up using traditional solution makeup techniques.

So where does in-line dilution fall in here? In-line dilution has a huge advantage compared to the large scale traditional processes because the mixing and preparation is actually being done at a small scale (think of the holdup volume of the skid vs. the 10,000L buffer prep tank). In addition, in-line dilution processes can incorporate feedback control and feedback control with mixing to achieve accuracies equal to or better than in the lab. As mentioned above, a process that was originally designed for a 10,000 L batch of process solution may now require twice as much solution due to increased yields. The manufacturing process now needs to make two 10,000 L batches in the preparation vessel and transfer each batch to a 20,000L storage vessel. Is there a 20,000 L vessel available? Is there room to install a tank this size?

Below is an illustration of this situation and how in-line dilution can solve this large scale problem.




What is automated in-line dilution?
In-line dilution is a process in which two streams are brought together in a controlled fashion to meet an overall target concentration. A dilution ratio of up to 10:1 or more can often be achieved by current equipment designs. This typically allows for product solution of up to a 10X concentration to be utilized. The maximum dilution ratio is limited by both equipment constraints and properties of the concentrated solution. Much larger dilutions can be obtained by placing multiple in-line dilution processes in series. The equipment utilized for an in-line dilution process is compact and usually portable. The equipment is typically only capable of performing one step at a time, meaning that only two inlet streams can be combined to make an intermediate or final product. If a second process step is necessary, such as addition of a third solution or adjustment of another parameter (i.e. pH), then a second module can be added to the equipment. Multiple skids can also be placed in series to accomplish this task. An intermediate is the output of any one in-line dilution module or skid. The intermediate is then directed to the inlet of the subsequent module or skid to perform the next processing step. Below is an illustration of a process in which multiple dilutions or processing steps can be performed.

Automation of the process allows for the final product solution to be manufactured “just in time” and the small portable equipment is capable of delivering the final product at the “point of use”. Below is a brief explanation of each of these terms:

Just in time – the product solution is manufactured on demand as required by the process in real time. The product does not require preparation prior to beginning the process and therefore eliminates the need for large storage vessels. This term originates from Six Sigma and Supply Chain Management as a method of reducing storage of intermediate products.

Point of use – the in-line dilution equipment can be placed at or near the point of use in order to eliminate intermediate storage tanks.

Portable – In-line dilution equipment can be designed as a “skid” system in which all of the components are fitted to a frame mounted on wheels. A portable skid makes transporting much easier and allows for the in-line dilution to be performed at the point of use, which could be in several areas of a facility.

Skid – A skid is a portable or semi-portable system that performs one or more unit operations and only requires simple utility hookups to operate. As an analogy, skids are to appliances as manufacturing plants are to homes.

Buffer – (Biopharmaceutical term) A process solution that is typically aqueous and contains one or more salts; the solution’s ability to maintain a stable pH value is implied but not necessarily valid.

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