In pharmaceutical industry enterprises, according to GMP standards, it is necessary to compulsorily carry out hygienic quality certification and legality measurement and appraisal of production equipment, production system and production process. In addition, the production environment (including air and indoor space) of pharmaceutical enterprises also has an important impact on product quality. Therefore, the hygienic quality of clean rooms must also be measured and identified.
Within the framework of health measurement and calibration, it is necessary to determine which measuring points and equipment must be measured and tested, so that the measurement and calibration can be carried out regularly. For the clean room in pharmaceutical production process, the equipment in the clean room must be measured according to the requirements of ISO 14644-3 standard Annex C. In all kinds of measurement and detection, the important measurement and detection instruments include: particle counter, aerosol detector, flow detector, differential pressure detector, thermometer and hygrometer, etc. Different sensor systems with appropriate detection accuracy will be used for different detection quantities. In addition, according to GMP standards, all testing instruments are required to be calibrated regularly. The standard stipulates that the calibration period of various testing instruments is 12 months. The technical feasibility in Annex C of ISO 14644-3 standard is transformed into the feasibility test of technical implementation in GMP standard.
Basic information of metrological calibration
The main basic concepts of metrological calibration are:
- Calibration of measurement: comparing the detection value with the standard value under the specified conditions;
- Correction: Adjustment of small possible differences;
- Units of measurement: Units specially designated for testing equipment;
- Standardization: The corresponding relationship between the data obtained in the continuous Metrological Inspection Process and the international standards;
- Uncertainty of testing: The parameters identified by the testing control system and related to the measurement results and the size of the measured values.
Normally, compliance is expressed by certificates of certification standards issued by different levels of national certification bodies. For example, the certification of DKD means that the requirements are met within the scope of DKD standard, because DKD certification is approved by the international standard certification and approval department. The purpose of metrological calibration is to check the consistency between the detected objects and the special standards. Only when the combination of detection error and reliability coefficient is less than the prescribed value can the certificate of consistency authentication be obtained. In the measurement and inspection, according to the requirements of the special technical specifications of the detected objects, the ratio of the unreliability of the measurement to the detection error should be 1:3. That is to say, when evaluating the results of measurement calibration, we should consider the factors of unreliability of detection.
Selection of Testing Instruments
In Annex C of ISO 14644-3 standard, the recommended instrument for measuring and calibrating according to ISO 14644-3 standard is given.
temperature
Resistance thermometer or thermistor should be selected as temperature sensor when monitoring room temperature. The required detection accuracy is 0.5 C. In today's production site or DKD measurement calibration, the measurement and inspection accuracy can reach 0.1-0.2 C. In Germany, there are more than 30 qualified DKD calibration laboratories.
relative humidity
According to the requirements of ISO 14644-3, humidity sensors with thin-coated capacitors or ^*** sensors should be used in relative humidity measurement. The detection accuracy of this kind of relative humidity sensor is required to be 2%-3% of RH value. Therefore, in the calibration of measurement, the reliability of the required detection is about 1%. In Germany, there are few qualified laboratories for relative humidity measurement and calibration, but they are sufficient for customers who require relative humidity measurement and calibration.
Pressure difference
In order to measure and monitor the pressure difference between clean rooms, it is necessary to measure the pressure difference within a lower differential pressure range (5-25 Pa). Beginning with 20Pa, more pressure balances must be used for calibration. In the low pressure range, in many cases only the difference compensation method can be used to estimate the consistency. Only a few laboratories can calibrate the low pressure difference.
Testo Industrial Services Co., Ltd. has developed a new calibration method for low pressure differential measurement. They use DKD-approved wind tunnel equipment. The principle is that the air flow through the wind tunnel will produce a certain pressure drop. By adjusting the air flow through the wind tunnel, a stable pressure difference can be obtained at the outlet of the wind tunnel while the air flow remains unchanged. The resulting pressure difference is about 5 Pa when the air flow rate is 3 m/s, and the measurement error is 0.2 Pa. This precision fully meets the requirements of calibration of commonly used pressure sensors.
Measurement of Airflow Velocity

There are also high requirements for the measurement of airflow velocity. According to the requirements of ISO 14644-3 standard, hot wire anemometer, supersonic anemometer and impeller anemometer suitable for low pressure airflow detection should be used. The measurement and calibration of anemometer with air velocity in the range of 0.45m/s are often carried out. The result of measurement calibration must prove that the error of anemometer is within (+20%). This requirement is difficult to meet, because according to the requirements of ISO 14644-3 standard, the technical specification of air anemometer in this case is 0.12m/s. In this case, only comparative measurement calibration can be carried out in order to achieve higher safety factor. At present, the measurement accuracy of three DKD calibration laboratories in Germany has reached 0.1m/s.

fine content
It is more difficult to calibrate the particle content measuring instrument. The allowable error of the particle content measuring instrument shall not exceed (+20%). At present, the DKD metrological calibration laboratory can not carry out this calibration work. The measurement and calibration of the particle counter can only be carried out in the instrument manufacturer. In accordance with ISO 17025, the Federal Authority can provide you with an observation method for the unreliability of the measurement and calibration of the particle content detector developed in Switzerland. The unreliability of measurement and calibration of particle content detector is relatively large when the particle content is low (about (+10%), so it is difficult to prove that it has met the requirement of (+20%) of the standard specification. That is to say, the traceability of calibration results is still insufficient in the measurement and calibration of particle content detector.
Summary: Generally speaking, the measurement and calibration of temperature and relative humidity measuring instruments have sufficient accuracy. In the low-speed air velocity range of 0-1m/s, due to the unreliability of the calibration results of the air anemometer, the number of units that can carry out the calibration of the air anemometer is too small. The calibration of a pressure difference detector with a pressure difference of 0-20 Pa is similar to that of an air velocity detector. As for the measurement and calibration of particle content detector, there is no DKD authorized measurement and calibration unit.
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