Precision Humidity Measurement for Pharmaceutical Fluid Bed Tablet Coating

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1 Precision Humidity Measurement for Pharmaceutical Fluid Bed Tablet Coating are several reasons why tablet cores are coated, including: Alpharma/Purepac is one of the largest global generic pharmaceutical companies with leading positions in the U.S. and Europe, selling over 500 products and doing business in over 60 countries. Alpharma/Purepac is also a leading provider of several key active pharmaceutical ingredients to major pharmaceutical companies around the world. One of the major pharmaceutical process functions that Alpharma/Purepac provides is fluid bed tablet coating. Tablet coating relies on producing accurate and reliable humidity controlled process air. GE Industrial Sensing has supplied Alpharma/Purepac with the model E4/HSS-12 heated chilled mirror and sampling systems. The heated chilled mirror is one of the best instruments for measuring humidity conditions where the dew point is above the ambient temperature. Most pharmaceutical tablets consist of a tablet core and a coated outer cover. The coating can be a variety of proprietary compounds. Various forms of sugar are major components of the coatings. There The core may taste unpleasant or bitter The core may become unstable due to the exposure to light The core may oxidize when exposed to the ambient atmosphere The core is pharmaceutically inelegant The core is processed with high speed packaging equipment and may become damaged The core is colored and might stain An enteric coating is used to modify the drug s time release. (Enteric pharmaceuticals have the ability to pass through the stomach unaltered and release in the small intestine) At Alpharma/Purpac s Elizabeth, NJ facility, fluid bed processing is used to coat a variety of products. Fluid bed coating utilizes a technique of suspending tablet cores in an air stream. The cores are mixed in a cyclic pattern past atomizing nozzles where the coating is sprayed on. The atomized coating material collides with the particles as they are carried away from the nozzle. The temperature of the fluidizing air is set to appropriately evaporate solution or suspension solvent or solidify the coating material shortly after colliding with the particles. The advantage of this process is the ability to provide a uniform coating. Precisely regulated flow rates, temperature, pressure and humidity is required to provide the optimum product quality and uniformity. All pharmaceutical process parameters must be validated to insure high product quality.

2 AIR EXHAUST PULSE AIR FILTERS ATOMIZING NOZZLE COATING SOLUTION PUMP PROCESS INLET AIR Fluid Bed Processor. The supply air is controlled to precise humidity and temperature levels. The fluid bed processor is constructed of stainless steel. The processing chamber is conically shaped. As process air flows through the bottom tablet cores are suspended. As the air travels upwards the diameter of the process chamber increases, resulting in a decrease in air velocity. As gravity overcomes the upward force, the tablet cores (or other pharmaceutical products) fall back. In this manner the product is mixed in a gentle fashion. The process air to the fluid bed is preconditioned by an air handling system. Outside air is filtered and cooled by either a direct expansion coil (refrigerant coil) or a chilled fluid coil. The chilled coil also serves to dehumidify the air. As moist air travels across a cooled surface, condensation occurs. Typically, the minimum dew point that is attained by chilled coils is +36 o F (+2ºC). If drier air is required, a desiccant dehumidifier is used. Air passes through a sorbent material (silica gel or alumina) in a rotating wheel and a portion of the wheel is regenerated by back purging with heated air. The injection of dry steam may also be used to increase the humidity to precise levels. Heating coils are used to heat the process air to prescribed conditions. Finally the process air is delivered though a HEPA (High Efficiency Particulate Arresting) filter to produce pharmaceutical grade air. In many fluid bed processes heat must be added for energy transfer. The water vapor pressure and therefore the latent heat of water vapor plays an important role in the adherence of coating materials and the evaporation rate of the carrier solution or SIM-12H Heated Chilled Mirror. The sensor is thermostatically controlled and indicated on a temperature gauge. The SIM-12H has a range of o F (0-85ºC) dew point (at a body control temperature of 185 o F/85ºC ). The sensor provides accuracy of ±0.1ºF ( ±0.2ºC) dew point. 2

3 COOLING COIL CHILLED MIRROR SENSOR 1111H-GE HEPA FILTER HEAT ER ROTARY DEHUMIDIF IER STEAM HUMIDIFIER INLET FILTER Components of an air handler used for pharmaceutical quality process air suspensions. Every recipe for tablet coating is different and many tablet coating and other fluid bed processing applications require humidified air where the dew point is greater than the ambient air temperature. Air which has a dew point greater than the ambient temperature represents a technical challenge for accurate measurement over the long term. A dew point sensor is often used within the air handling system to regulate the dew point or absolute humidity (absolute humidity is defined as the mass of water vapor per unit of volume of dry air, commonly measured in g/m3 or grains/ft3). A chilled mirror sensor is typically the humidity sensor of choice because of the fundamental nature of the measurement and its drift free characteristics. GE s DEW-10 series chilled mirror transmitters or 1111H-GE are recommended for air handler control. These instruments provide either a direct RTD output or a 4-20mA signal that is fed to the air handler control system. Since the process air is pharmaceutical grade and the reaction vessel has to have the ability to be cleaned out with steam, an insertion type sensor is not desirable. For measurement of process air downstream of the HEPA filter a sampling system is recommended. In many applications the air might be heated to as high as 185 o F (85ºC) with dew points to 149 o F (65ºC). This is often a region of humidity measurement where many polymer based %RH sensors fail within the short-term. Since the dew point of the process is higher than the ambient temperature a heated sampling system must be used. A properly designed heated sampling system will not alter the dew point temperature. If the sampling system were not heated water would condense in the sampling lines altering the measurement. Maintaining the temperature of all of the sampling components (PTFE sample tubing, filter, rotameter etc) is of primary importance. 3

4 GE s Ken Soleyn, Metrology Product Manager, and Sunil Shah, Senior Applications Engineer, discussed the application with Alpharma/Purpac s James Feschak, Supervisor of Instrumentation/Calibration and Bill Harding, Instrumentation Technician. Once the process parameters were reviewed, it was determined that GE s model E4/HSS-12H chilled mirror analyzer with heated chilled mirror sensor and sampling system was the best instrument suited to the application. The system is a time proven solution for many industrial and research applications where high humidity levels are measured. The HSS-12 sampling system consists the following components: SIM-12H: Heated Sensor Module. The sensor measures dew/frost points between 14 o F and 185 o F ( 10 C and +85 C). It contains precision heating, as well as cooling, capability. Three separate heaters are located in the sensor walls 120 degrees apart. Three temperature sensors measure the body temperature at those points, and three control circuits precisely adjust the temperature of each heater. Any detected temperature gradient across the sensor cavity is immediately eliminated, resulting in very even control. All three heaters are controlled by the temperature set by the front panel selector knob. The sensor is a two- HSS-12 Heated Chilled Mirror Sensor & Sampling System How Does a Chilled Mirror Measure Humidity? Chilled mirror dew point sensors measure dew point temperature directly by cooling a reflective surface by utilizing a thermoelectric heat pump such that a dew or frost layer condensed on the metal mirror is controlled to a constant mass. The surface is made of either polished rhodium or platinum. A temperature is maintained such that the mass of water vapor condensing and evaporating is at an equilibrium. This is accomplished by incorporating feedback control loop from an optical detector. The polished surface or mirror is illuminated by a GaAs infrared emitter. When the mirror is dry virtually 100% of the signal is received by a photodetector. A second pair of emitter/detectors is used as a reference. When water condenses on the mirror as dew or frost, the IR light scatters and the decrease in signal is used by a servo control to regulate the power to the thermoelectric cooling module. A precision 4-wire platinum RTD imbedded in the mirror block is used to measure the temperature which is by definition equal to the dew/frost point temperature. The system provides fundamental NIST traceable humidity measurement. Since the wetted components of the chilled mirror sensor are inert, the sensor is characterized by having minimal long-term drift. Typical accuracy is ±0.1ºF (±0.2ºC). The dew point measurement along with simultaneous temperature and pressure measurements may be converted by an analyzer to other humidity parameters such as relative humidity, absolute humidity, mass mixing ratio, volumetric mixing ratio, enthalpy and wet bulb temperature. 4

5 stage unit, providing 149 o F (65 C) cooling depression at 77 o F and 140 o F (25ºC and 60 C) actual measurement range. SIM-HFT: Heated Filter Module allows the sample gas to be filtered from of particulate contaminants prior to entering the sensor. The incoming gas is first passed through a 90-micron prefilter then a 15-micron final filter. All parts in contact with the sample gas are heated to a constant 221 o F (105 C). This eliminates any possibility of condensation. The sintered filters are easily removed for cleaning or replacing if required. SIM-HFM: Heated Flow Meter Module allows the sample gas flow rate to be both measured and controlled at a rate that is optimum for the sensor. A metering valve mounted on the front panel allows control over a range of 0 to 2 ft 3 /h. All parts in contact with the sample gas are heated to a constant 221 C (105 C), so that no condensation occurs. The flowmeter is normally mounted downstream from the heated sensor. SIM-HSL: Heated Sampling Line is self-regulated at a temperature high enough to ensure that no condensation occurs. It is stocked in standard 15-foot lengths, and longer lengths are available on special order. The line is made of 1/4-inch outside diameter PTFE with stainless steel fittings. SIM-MPL: A mounting plate is designed to accept the three heated modules: the heated sensor, the heated filter, and the heated flow meter. The mounting plate provides a convenient method of wall-mounting the entire heated sampling system. GE performs all mounting, plumbing and wiring work, thus providing a turnkey system ready for installation. The heated sensor is connected to a E4-RH analyzer which provides display, alarm output, a linear 4-20mA analog signal and RS-232 digital interface. The analog output is connected to the air handler control and data acquisition system. The instrument is delivered with a certificate of calibration to NIST traceable standards. The certification also includes functional GE s Optica series chilled mirror analyzers and sensors. Chilled mirrors are used for calibrating other types of humidity instruments as well as in mission critical applications where drift cannot be tolerated.the Optica instruments provide analog and digital outputs as well as local indication of the process parameters. These instruments feature a programmable IP address with an Internet interface. This enables data as well as diagnostic parameters to be accessed via a LAN or the internet. The Optica also features a 6 MB data logger, enabling process parameters to be documented over the long term. 5

6 test data which compares the readings of the dew point instrument against a transfer standard. Alpharma/ Purepac contracted for GE s Sunil Shah, Senior Application Engineer, to provide onsite training and start up installation assistance. Mr. William Harding provided the following comments; I wanted to take a few minutes to thank you and express our satisfaction with the training you provided at our facility on Feb 20, After discussing the training with the others that attended, we feel that we have a greater understanding of humidity and the chilled mirror system. Pharmaceutical processing must be validated under FDA (Food & Drug Administration) guidelines and must be documented with a full package of test plans, procedures and certifications. Any deviations from the manufacturing process must be documented; therefore the industry relies on quality NIST traceable instruments such as GE s chilled mirror hygrometers. Fluid bed processing is used in a wide variety of applications in the pharmaceutical, food and chemical industry. A wide variety of products such as powdered soft drinks, candy, copier toner and soap powders are processed in fluid beds. 6