Maintaining and Verifying Clean Room Differential Pressure in a Pharmaceutical Manufacturing Environment

In most large-scale FDA-regulated pharmaceutical manufacturing operations, it is required that the product be manufactured in a clean room classified between Class 100 and Class 100,000. In an operation where medical tubing is being extruded, the classification would likely be Class 100,000. In a process where inject-able drugs are being manufactured, the classification would most likely be Class 100 or Class 1000.

The purpose of the clean room is to eliminate contamination by dirt particles, some of which potentially contain microorganisms or toxins, and to provide a controlled physical environment with respect to temperature, pressure and humidity. Controlling these three parameters is no easy task. The intake air must be filtered and moisture and/or heat added or removed as required. Large fans located above the clean room force air through an elaborate filtering system. Air also needs to be used to remove contamination introduced by the occupants and materials taken into the clean room. The location of vents is important to provide proper circulation. The air is humidified or dehumidified and heated or cooled, depending upon the signals transmitted from the monitoring humidity and temperature sensors.

Of the three parameters being measured, pressure is critical to the proper functioning of the clean room. If the pressure is too low, especially when a door is opened, contaminants can enter. If it is too high, energy is being wasted. In the case of a biotech lab where a possibility exists for the release of pathogens, a negative pressure is normally required. If this negative pressure differential is lost, this containment breach could result in release of the pathogens into adjacent areas.

Most clean room pressure transmitters operate at very low pressure differentials, normally in the range of 0.1 to 0.25 inH 2O. These sensors are sensitive to position and will change output if the orientation is disturbed. Some companies remove these devices and send them to a metrology lab for calibration. The act of removal and reinstallation completely invalidates the calibration. In the case of variable capacitive devices, a change in humidity can also impact the calibration.

There are many companies that provide calibration services. For the pharmaceutical company, this may appear to be a perfect solution. The elimination of in-house systems and personnel can reduce overhead costs. For the smaller manufacturing operation this seems feasible. The concept of third-party culpability ‘in case something goes wrong’ has some merit, but it does not eliminate the manufacturer’s ultimate responsibility. A case in point: A small pharmaceutical company was using a service company to calibrate their ±0.25 inH 2O range sensor, which had an absolute accuracy of ±0.00125 inH 2O. For calibration, the service provider, in error, used a 200 inH 2O calibrator that had an accuracy of ±0.05%FS (an absolute accuracy of ±0.1 inH 2O) or one-tenth the accuracy of the sensor being calibrated! Someone “signed off” on the calibration and the plant manager, who was focused on the calibration being conducted within schedule, wasn’t aware of the problem.

 

 

 


 

GMP (Good Manufacturing Practice) dictates that low differential pressure devices a (±0.25 inH 2O) be calibrated in place to eliminate orientation errors. To calibrate in place, it is necessary to have a portable calibrator with a recommended 4X accuracy. In actuality, there is no portable device presently available that will provide this accuracy (±0.00125 inH 2O). The Druck DPI 615LP offers a full-scale pressure range of ±1 inH 2O with an accuracy of ±0.05%FS resulting in an absolute accuracy of ±0.001 inH 2O. This is the best presently available. The only other device available that is more accurate is the Pressurements V1600D Deadweight Tester with an accuracy of ±0.0004 inH 2O. It, however, is a laboratory instrument.

The DPI 615LP is a documenting calibrator that allows all of the measurement data to be collected into its data logging memory and later downloaded into a computer (to maintain a documented control system which is required by ISO 9000 as well as the FDA). Additionally, the sensor information can be uploaded so that the operator needs only to highlight the proper serial or tag number and perform the measurement. Pass/fail information can also be programmed enabling the on-site operator to determine if the device needs to be replaced or adjusted. This calibrator completely eliminates the problem of human error when recording data. An internal dual piston pressure generator allows the pressure to be generated within the calibrator, thus eliminating the need for external variable volume devices.

The DPI 615LP also has a pressure switch calibration routine in which the operator only has to pressurize the switch until it switches and then release the pressure. The calibrator stores the switch points as well as the hysteresis.

The leak detection feature allows the set up of timing and range to be pre-programmed, thus eliminating any confusion on the part of the operator.

The DPI 615LP interfaces with many of the most popular documentation software programs, enabling long term monitoring of accuracy. Statistical documentation of long term stability and drift is important to establish a credible criterion for pressure sensor performance. The current practice is to calibrate the pressure sensor and readjust zero and span if required. If this is a chronic event, it could indicate that the device is not capable of maintaining the integrity of the clean room. In GMP this documentation is important in weeding out poor performing sensors before they allow an environmental breach.

Druck manufactures a broad range of pressure sensors including low-pressure wet/wet differential sensors for clean room monitoring and control. Druck is the largest manufacturer of portable field pressure calibrators.

 

 


Content for this article was provided by GE DRUCK


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