  Every cleanroom has environmental-control specifications that define the upper and lower limits for temperature and relative humidity (RH). Pressure, flow, and contamination must also be controlled. Devices that measure RH (e.g., sensors and transmitters) play a relatively small role in cleanroom management, but their failure can cause significant problems. Operators should bear several factors in mind to ensure that sensors function properly and maintain the appropriate humidity.
   
  

The fact that RH depends on temperature affects the placement and installation of RH sensors. For example, if only 50 mm of an instrument’s 200-mm stainless-steel probe is exposed to the process air, the rest of the probe may serve as a heat sink or source, depending on its environment. Thus, the temperature of even a carefully designed humidity-sensing element can change and cause an RH measurement error that depends on the difference between the process-air temperature and the environment surrounding the exposed portion of the probe. This error is easily measured in a laboratory environment.
   
  Because local heating can affect wall-mounted RH instruments’ measurements, operators should install the devices away from equipment that generates heat. Good airflow in the cleanroom usually minimizes convective-heat problems, but warm or hot equipment radiates heat, potentially creating a temperature discrepancy and corresponding measurement error. Loop-powered devices with a 4–20-mA output dissipate some power as heat, and this dissipation could affect wall-mounted RH instruments. Some wall-mounted RH devices housed in enclosures heat themselves by several degrees and experience significant measurement errors. RH devices with short probes that isolate the humidity-sensing element from the instrument’s electronics preclude this possibility.
   
  Humidity sensors should be protected from moisture. They should be located far enough from cooling coils so that they are unlikely to be affected by entrained water droplets. The sensors also should be kept away from steam-injection or ultrasonic-humidification elements. Many RH probes incorporate filters that eliminate catastrophic errors by protecting the sensing element from water. Water can accumulate on or in the filter material, however, and create a microclimate around the sensor that results in measurement errors. 
   
  In all of the situations described above, measurement errors result from subtle factors that change over time or occur only seasonally. These situations are among the most difficult to remedy when the sensor has been installed in an inappropriate location. If the errors are big enough to create out-of-specification conditions, they will trigger service calls, calibration requests, and equipment replacement. Personnel can prevent these potentially expensive problems during the design and specification processes for RH sensors.
   
  

The instrument-specification process is a good time to think about the accuracy specifications of the various RH sensors available. No standard requirement for accuracy has been established, so manufacturers must consider their specific applications to determine the accuracy specifications they need.
   
  Although they are important criteria, accuracy specifications should not necessarily be the decisive factors for RH instruments. Sensor vendors emphasize these specifications, but performance claims can sometimes be misleading because “accuracy” is a qualitative term in measurement science that includes uncertainty. 
   
  

Long-term stability is easily the most important performance characteristic of an RH instrument. 

is the instrument’s ability to make accurate measurements consistently over a long period of time. Reputable vendors perform long-term tests to characterize their own devices. The results of these tests help personnel understand the sensors’ baseline performance, but the performance in individual cleanrooms may be different because of the cleanrooms’ unique conditions.
   
  The most significant threat to the long-term stability of an RH instrument in a cleanroom comes from vapors from the chemicals used in cleanroom processes. Vapors cause incorrectly low RH readings in high-humidity conditions because the vapor blocks water molecules from reaching the sensor. In low-humidity conditions, vapors cause incorrectly high RH readings. Some RH devices are equipped with features that minimize the effect of chemicals. For example, a chemical-purge function heats the sensor quickly to a high temperature (e.g., 160 °C), and thus cleans it of unwanted vapors.
   
  

Many humidity-measurement problems in a cleanroom such as sensor drift can be anticipated and prevented with thoughtful planning. Care should be taken throughout the entire RH-instrument specification and installation processes. Correct installation location, protection from moisture and vapors, and the instrument’s long-term stability should be taken into account to ensure optimal sensor performance.
   
  

Jim Tennermann is a regional market manager for controlled-environment products at Vaisala, 10-D Gill St., Woburn, MA 01801, tel. 888.824.7252, fax 781.933.8029, 

Articles

In the Mixer

Devices that measure relative humidity (e.g., sensors and transmitters) play a relatively small role in cleanroom management, but their failure can cause significant problems. Operators should bear several factors in mind to ensure that sensors function properly and maintain the appropriate humidity.

Ensuring Accurate Humidity Measurement in Cleanrooms

  Establishing a common goal is sometimes far easier than reaching an agreement about how to achieve that goal. Drugmakers have the common goal of manufacturing safe and sterile pharmaceutical products and understand that the filtration process is a critical means of achieving this goal. Preuse filter-integrity testing provides evidence that a filter will perform correctly, has the right pore size, and has been installed correctly. The European Commission requires this testing in Annex 1 of its good manufacturing practice (GMP) guidelines, and European inspectors are increasing their enforcement of the requirement, according to Michiel Rook, biopharmaceutical consultant and independent filtration expert at Global ConSeptS Consultancy (1). The US Food and Drug Administration, however, does not require preuse integrity testing, and some industry professionals question the need for it.
   
  Those who argue against the need for preuse integrity testing point out that most filter vendors test the integrity of their products before they are shipped from the manufacturing facility. Filters could be damaged during transportation to the pharmaceutical company, however, and preuse integrity testing can detect this damage. Yet the chance that a filter would be damaged during transportation is “almost zero,” says Rook. Even disposable filters are now shipped in strong packages that withstand rough treatment, he adds.
   
  Preuse integrity testing can also detect filter damage that occurs during steam sterilization, which is the most common cause of filter failure, says Maik Jornitz, group vice-president of marketing and product management for Sartorius Stedim North America (Bohemia, NY). But validating steam-sterilization cycles as required and staying within the filter manufacturer’s specifications should reduce the likelihood that such cycles will damage a filter, Jornitz says.
   
  Some argue that the nature of the filtration process itself makes preuse integrity testing worthwhile. During filtration, a filter captures particles on its surface or within its matrix, says Russell Madsen, president of The Williamsburg Group and a member of 

’s editorial advisory board. Particle entrapment decreases the filter’s porosity and diffusive flow, potentially leading personnel to believe that the filter integrity is greater than it actually is. In the absence of a preuse integrity test, a defective filter could conceivably allow bacterial penetration but pass a postuse test because of particle entrapment, says Madsen.
   
  This situation is unlikely to occur, says Jerold Martin, senior vice-president of scientific affairs at Pall Life Sciences (East Hills, NY). “Particle loads are generally too low to plug filter defects large enough to allow bacterial penetration and cause false-pass integrity tests of nonintegral filters,” he says. Particulate and bioburden loads in presterilizing filtration feeds are typically low, especially during serial filtration. In addition, before a filter is shipped to a drugmaker, the filter manufacturer validates it to ensure that its pore structure does not change during sterilization and tests it to exclude oversized pores. 
   
  Some pharmaceutical manufacturers are averse to preuse integrity testing because it entails many changes to the downstream side of the filtration line. A filter must be flushed and wet before integrity testing, and the wetting fluid must be sent to a drain or contained in a tank or plastic container. Sterile air must be introduced to the filtration line, and the downstream side of the system must be maintained at atmospheric pressure without breaching the system’s sterility. These preparations can create a “Christmas tree” of additions to the filtration line, says Rook. “The more steps you add, the more manipulation you do, the more chance you breach the sterility,” he says.
   
  But preuse integrity testing need not compromise downstream sterility. Instead of a manual integrity test that poses greater risk because it requires downstream manipulation, operators can use an automated instrument that performs the integrity test on the upstream side of the filter. Automated upstream integrity tests will not cause loss of downstream sterility, provided the filter is integral, says Martin.
   
  Regulators should allow manufacturers to decide whether to perform preuse integrity testing, says Jornitz. Flawed filters are detected after filtration, and filtered product can be reworked or discarded, depending on its cost and whether the reprocessing is validated. “It’s an economic decision, not one involving higher safety,” Jornitz says. Modern filters are robust, and failures are uncommon, he adds. 
   
  Yet variables such as transportation, installation, and sterilization are significant enough to prompt some drugmakers to take the extra precaution of performing preuse integrity tests. These variables might have influenced the European Commission to mandate the tests. The future harmonization of regulatory standards might one day provide a single official answer to the question of whether the tests are needed to ensure drug and patient safety.
   
   
  

EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use Annex 1 Manufacture of Sterile Medicinal Products 

http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol4_en.htm

Production Lines

Drugmakers have the common goal of manufacturing safe and sterile pharmaceutical products and understand that the filtration process is a critical means of achieving this goal. Preuse filter-integrity testing provides evidence that a filter will perform correctly, has the right pore size, and has been installed correctly.

The Debate over Preuse Filter-Integrity Testing

Mettler Toledo Safeline
 Metal detector offers high sensitivity


 Mettler Toledo Safeline’s (Tampa, FL) Pharma GF gravity-fall metal detector incorporates an ultrahigh-frequency coil system and sophisticated digital noise and vibration filtering techniques to provide a high level of detection sensitivity, particularly to nonmagnetic stainless steels. The unit detects irregularly shaped metal contaminants such as sieve wire and slivers.

The detector also provides stable performance through its immunity to external interference and vibration. 
 

The Pharma GF is a fully integrated system that includes a high-speed reject diverter and built-in performance-validation routines that support regulatory compliance. Systems also include software that automatically checks that the system’s critical components are operating correctly and alerts operators if problems occur. The detector can be integrated with data-collection and network-connectivity solutions to enable compliance with 21 

Part 11. The Pharma GF unit is made of mirror-polished stainless steel and is suitable for the inspection of free-flowing pharmaceutical powders.

Munters 
 Heat exchanger operates at high temperatures


 The Thermo-Z welded-plate air-to-air heat exchanger from Munters (Buena Vista, VA) can be constructed with integral, all-welded, stainless-steel expansion joints that are designed to account for the internal thermal growth of the plate pack. Expansion joints allow the heat exchanger to thermally expand in all directions inside the exterior case. The exterior case and the connection flanges are isolated from the heat and will not thermally expand. This feature facilitates installation, according to the company. 
 
Thermo-Z units are available with various cleaning options for applications such as water-wash systems. The devices can be constructed of corrosion-resistant materials and designed for retrofit applications. The heat exchangers achieve effectiveness as high as 85% and function at operating temperatures as high as 1400 °F. The Thermo-Z unit is appropriate for recovering energy from a dryer or applications operating with elevated waste airstreams.

PharmTech's monthly newsletter, Equipment & Processing Report, reviews the Editor's Picks for the July 2009 edition from Mettler Toledo Safeline and Munters.

Equipment and Processing Report-07-22-2009

Ensuring Accurate Humidity Measurement in Cleanrooms

The Debate over Preuse Filter-Integrity Testing

July 2009 Editor's Picks: Products from Mettler Toledo Safeline and Munters