Drug packaging material factory inspection

Reference standard YBB-2015 for testing of pharmaceutical packaging materials in clean rooms (areas) of pharmaceutical packaging materials production plants: (1) Testing of temperature and relative humidity, (2) Testing of air exchange rate, (3) Testing of cross-sectional average wind speed, (4) Testing of airflow pattern, (5) Testing of pressure difference and pressure gradient, (6) Testing of suspended particles, (7) Testing of planktonic bacteria, (8) Testing of settling bacteria, (9) Testing of illuminance, (10) Noise, (11) High efficiency filter leak detection photometer method

Introduction to Testing Methods

Reference standardsYBB-2015Testing methods for clean rooms (areas) in pharmaceutical packaging material production plants

（1）Testing of temperature and relative humidity

①Before testing, the air purification system should have been running continuously at least24When the system is in a stable and normal operating state, the testing personnel should also pay attention to standing on the downwind side of the testing instrument during sampling and try to be as inactive as possible.

②If the local area is a constant temperature and humidity area, it must be noted in the test record, and sampling points and calculation deviations must be arranged according to regulations. The sampling points are arranged as follows: if it is not a constant temperature and humidity clean room (area), the sampling points are off the ground0.8mDistance from the wall0.5mThe indoor center position; If it is a constant temperature and humidity clean room (area), it should comply with the following regulations:

a.The interval between each test shall not exceed30minute:

b.The layout of indoor sampling points should include representative locations such as the return air outlet and the constant temperature working area (e.g. arranged around the process equipment or equidistant):

c.Sampling points should generally be arranged at a distance greater than the wall surface0.5m, off the ground0.8mAt the same height, it can also be arranged on several planes at different heights above the ground according to the size of the constant temperature zone;

d.The number of sampling points should comply with the table1regulations.

table1 Sampling points for temperature and relative humidity

③Use direct reading method to evaluate the temperature and relative humidity of the clean room (area). If a digital temperature and relative humidity meter supported by electronic components is used, the instrument should be preheated to stability before calibration can be carried out according to the instructions in the instrument manual, and the corresponding testing range should be selected. It is advisable to keep the testing probe of the temperature and relative humidity meter as close as possible to the sampling point in a horizontal plane. Testing can only begin after confirming that the reading is stable.

④The outdoor temperature and relative humidity values should be tested simultaneously.

⑤For clean rooms (areas) without constant temperature and humidity requirements, the sampling data of temperature and relative humidity are compared with the standard to determine whether they are qualified or not. For clean rooms (areas) with constant temperature and humidity requirements, the judgment of whether the temperature and relative humidity meet the standards should simultaneously meet the following requirements: the fluctuation range of room temperature should be consistent with the temperature value of the deviation control point in the temperature test data of each sampling point, and the percentage of it to the total number of sampling points should be compiled into an accumulation statistical curve. If90%If the deviation values of the above sampling points are within the fluctuation range of room temperature, they are in compliance with the regulations. Otherwise, they are unqualified. The fluctuation range of relative humidity can be executed according to the regulations of room temperature fluctuation range.

⑥If testing two or more items at the same time, temperature and relative humidity testing should be conducted to comprehensively evaluate the impact of temperature and relative humidity on other items: too low relative humidity can cause static electricity problems, causing dust to adhere to metal surfaces, while too high relative humidity significantly increases the risk of microbial contamination. For humidification treatment in clean rooms (areas), high-quality water should be used to avoid contamination.

（2）Test of air exchange rate

①For non unidirectional flow clean rooms (areas), test the air supply volume of each air outlet to convert the air exchange rate.

②Using an air balance thermal radiation measuring instrument or air volume hood, directly read the air supply volume value of each air outlet（m2/m）The sum of the air supply volume of all air supply outlets in the clean room (area) is the air supply volume of the clean room (area).

③For non unidirectional flow clean rooms (areas), the air supply volume can also be determined using the vent method or duct method, as follows.

a.The air outlet method is used to measure by connecting auxiliary air ducts according to the shape of the air outlet at the air outlet where a high-efficiency filter is installed. Made of galvanized steel sheet or other dust-free materials with the same shape and inner cross-section as the air outlet, with a length equal to2A straight pipe section with a length of twice the length of the air outlet, connected to the outside of the air outlet. On the outlet plane of the auxiliary air duct, the minimum number of sampling points shall not be less than6Arrange sampling points evenly and use an anemometer to measure the range of each sampling point within the boundary of the air supply outlet0.05mThe area within the range is calculated by taking the arithmetic mean of the wind speed readings at all sampling points as the average wind speed, and then multiplying the average wind speed at the air supply outlet section by the net cross-sectional area of the air supply outlet to obtain the air volume.

b.When there is a long rectangular branch pipe section on the windward side of the air outlet, and it has been or can be drilled, the air duct method can be used to determine the air volume. The measurement section should be located in front of the component with local resistance greater than or equal to3The part with double the diameter or long side length of the diameter can also be the part behind the local resistance component5For circular ducts with double diameter or long side length, the cross-section should be divided into several concentric rings with the same area according to the size of the diameter, and each ring should have4Sampling points, the number of circular rings should not be less than3For rectangular ducts, the duct section can be divided into several equal small sections, with each small section as close to a square as possible and a side length not greater than200mmTake the center point of each square as the sampling point to test the wind speed value, but the number of sampling points on the entire cross-section should not be less than3Take the arithmetic mean of wind speed readings from all sampling points as the average wind speed; Then, the air supply volume is calculated by multiplying the average wind speed of the air supply outlet section by the net cross-sectional area of the air supply outlet.

（3）Testing of cross-sectional average wind speed

Use an anemometer for direct testing. The wind speed is0.36~0.54m/s(Guidance value).

①For vertical unidirectional flow cleanrooms, remove the high-efficiency filter during testing0.3mThe section perpendicular to the airflow is taken as the sampling section. For a horizontal unidirectional flow clean room, the sampling point should be taken at a distance from the air supply surface during testing0.5mOn the vertical section, the spacing between sampling points on the section should not be greater than0.6mEvenly distribute points; The number of sampling points should not be less than5One.

②When testing wind speed, it is advisable to use a measuring frame to fix the anemometer to avoid human interference; If it is necessary to use a handheld anemometer for testing, the arm should be extended to the longest position and the human body should be kept as far away from the sampling point as possible; It should be noted during specific operation that there should be no obstructions in front and behind the testing components of the testing instrument when testing the cross-sectional wind speed, otherwise it will result in inaccurate data or inability to measure the wind speed.

③Take the arithmetic mean of wind speed readings from all measuring points as the average wind speed of the section, and compare the value of the average wind speed of the section with the standard to determine whether it is qualified or not. The average wind speed of the cross-section is in accordance with this standard“test method”Under the item（2)item“Test of air exchange rate”in“Average cross-sectional wind speed”conduct.

（4）Airflow pattern detection

The purpose of this test is to confirmAGrade orBThe airflow pattern in the level area and the airflow direction between the clean room and adjacent areas. Method according toISO14644.3《Cleanrooms and associated controlled environments-Part 3 Test Methods》In the middle4.2.5termsAirflow direction test and visualizationMid Test ProgramB7conduct.

ForAGrade orBThe airflow pattern test in the level area adoptsMSP-2010Airflow visualization tester testing. Translate into EnglishMSP-2010The airflow visualization test is only filled with injection water, and the steam flow rate is adjusted to4rise/After minutes and reaching stability, place the columnar steam flow in laminar flowLAFSlowly move horizontally, observe the flow direction of the columnar steam flow, record and document it with digital images, and confirm whether the airflow pattern meets the acceptance criteria; For the airflow direction test between the clean room and adjacent areas, an airflow direction test rod is used to release smoke at the gap between the clean room and adjacent areas. Digital images are recorded and documented to confirm compliance with acceptance standards.

（5）Testing of pressure difference and pressure gradient

The pressure difference defined in this standard is the gas pressure difference between the clean room (area) being tested and the adjacent area or adjacent outdoor atmosphere.

The pressure difference test should be conducted after the air volume balance adjustment is completed. To measure the pressure difference between adjacent areas, a micro differential pressure gauge was used throughout the entire testing process. When measuring, all doors must be tightly closed, and then gradually measured from the innermost part of the clean room outward. The pressure difference of each room relative to all other rooms or areas should be measured, and special attention should be paid to the direction of the pressure difference between each measuring point and its adjacent position. At the same time, the pressure gradient should be indicated on the airflow direction diagram.

If there is an acceptance standard for the pressure difference between adjacent rooms or areas, it should be expressed in specific numerical values. If there is no pressure difference requirement, it should be expressed in numerical values“/”express:“+”Then it means“room”The pressure is higher than“relative position”The region;“one”Then it means“room”The pressure is lower than“relative position”The area. During testing, try to stay away from the air supply and return ports or other factors that may affect the measurement of pressure difference. For clean rooms with non closable openings that are connected to adjacent rooms, the pressure difference at both ends of the opening, airflow velocity, and airflow pattern should also be tested.

①If a pointer type micro differential pressure gauge is used, the direct reading method should be adopted, and the gas pressure in the clean room (area) and adjacent areas should be evaluated based on the measured pressure difference. If other micro differential pressure gauges are used, the level should be adjusted first to confirm compliance before proceeding. If a digital micro differential pressure gauge supported by electronic components is used, the instrument should be preheated to stability before calibration can be carried out according to the instructions, and the corresponding testing range range should be selected.

②If possible, it is advisable to align the connecting tube of the micro differential pressure gauge with the horizontal plane of the sampling point as much as possible, and the sampling point should be located approximately above the ground0.8mOn a horizontal plane at a height, select a position without eddy currents or return air vents, and start testing after confirming that the readings are stable.

③The sampling data of the pressure difference value should be compared with the standard to draw a conclusion on whether it is qualified or not. At the same time as testing the pressure difference value, the ventilation rate or cross-sectional wind speed of the tested clean room (area) should be combined to facilitate a comprehensive evaluation of the clean room (area),AGrade（ISO Class5）If necessary, the cleanroom (area) with the above cleanliness levels should be monitored inside the door when opening it0.6mThe concentration of suspended particles in the area.

（6）Testing of suspended particles

The counting concentration method is used to evaluate the cleanliness level of a clean room (area) by measuring the number of suspended particles with a particle size greater than or equal to a certain particle size per unit volume of air in the clean environment. The testing method adoptsISO14644.1《Cleanrooms and asociated controlled environments-Part 1 Classification of air cleanliness》AndGB/T16292-2010Testing method for suspended particles in clean rooms (areas) of the pharmaceutical industry. To confirmAThe level of the clean area shall not be less than the sampling amount of each sampling point1m³.AThe level of suspended particles in the air of the cleanroom isISO4.8, in order to≥5.0umThe suspended particles are the limit standard.BThe level of suspended particles in the air of the cleanroom (static) isISO5, including suspended particles of two different particle sizes listed in the table. ForCIn terms of clean areas (static and dynamic), the levels of suspended particles in the air are as follows:ISO7andISO8ForDThe level of suspended particles in the static air of the cleanroom isISO8.

The testing method is as follows:①Minimum number of sampling pointsNL=in the formulaNLTo minimize the number of sampling points:AFor the clean room or controlled clean area area,m2

Note: In the case of horizontal unidirectional flow, the areaAThe cross-sectional area perpendicular to the direction of airflow.

During static testing, the sampling point is above the ground0.8mUniformly arranged on a high horizontal plane. Sampling at each point2~3Next time.

（7）Testing of planktonic bacteria

The counting concentration method is used to determine the microbial concentration in the cleanroom by collecting suspended biological particles in a specialized culture medium and allowing them to reproduce to visible colony counts under suitable growth conditions for a certain period of time.

The testing method adoptsGB/T 16293-2010Testing method for planktonic bacteria in clean rooms (areas) of the pharmaceutical industry

1. The minimum number of sampling points for planktonic bacteria testing can refer toGB/T 16292-2010Testing method for suspended particles in clean rooms (areas) of the pharmaceutical industry.

2. Location of sampling points

A)The location of the measuring point in the work area is off the ground0.8m～1.5mLeft and right (slightly higher than the working face);

B)The measuring point of the air supply outlet is located away from the air supply surface750px左右；

C)Measurement points can be added at critical equipment or critical work activity areas.

3. Minimum Sampling Quantity

The minimum sampling amount of planktonic bacteria per time is shown in the table2.

table2

Note: Each sampling point is generally sampled once.

4. Sampling precautions

A)For unidirectional flow clean rooms (areas) or air supply outlets, the sampling port of the sampler should face directly in the direction of the airflow; For non unidirectional flow cleanrooms (areas), the sampling port should be facing upwards.

B)When arranging sampling points, at least try to avoid the return air outlet where dust particles are concentrated.

C)During sampling, testers should stand on the downwind side of the sampling port and try to walk as little as possible.

D)All measures should be taken to prevent contamination during the sampling process and other potential contamination of the sample.

(8)Testing of Settling Bacteria

Adopting the sedimentation method, which collects biological particles in the air through the principle of natural sedimentation and incubates them in a culture dish. After a certain period of time and suitable growth conditions, they are allowed to reproduce until they form independent and visible colony counting criteria to determine the microbial concentration in the clean room (area).

①The sedimentation bacteria test generally uses flat petri dishes of equal specifications, or suitable petri dishes can be selected according to process requirements.

②Preparation and sterilization of culture medium, preparation of culture dishes, and cultivation before use of culture dishes shall be prepared using the same method as the planktonic bacteria test in this standard

③The arrangement of sampling points for settling bacteria in the clean room (area) during static testing should follow the principle of uniformity and comprehensiveness, avoiding excessive concentration of sampling points in a certain local area, unless for special purposes. The sampling point in the workspace is located off the ground0.8~1.5mLeft and right, leave the air supply side750pxDuring dynamic testing, sampling points can also be added at critical equipment or critical processes. The position of the sampling point can be the same as that of the suspended particles, and each sampling point should be sampled at least once.

④For unidirectional flow clean rooms (areas), sampling should be directed towards the airflow direction. For non unidirectional flow clean rooms (areas), the culture medium petri dish should be opened upwards during sampling, and the return air outlet with concentrated dust particles should be avoided appropriately. Testers should also stand on the downwind side of the sampler nozzle during sampling.

⑤Before conducting the test, the culture dish used should be inspected to confirm that there are no bubbles, dents, bacterial growth, and within its validity period. The outer surface of the culture dish must be wiped clean with disinfectant before use.

⑥After sampling, invert the culture dish and incubate it in a constant temperature incubator（35℃±2℃,48h）.

(9)Illumination testing

The illuminance value defined in this standard is the indoor illuminance value of the clean room (area) being tested. Adopting the direct reading method, that is, by measuring the illuminance values of various points in the clean environment and selecting the illuminance values from them, the illuminance of the clean room (area) can be evaluated.

①Illuminance testing should be conducted when the light source output tends to be stable and natural lighting should be avoided as much as possible. If there is local lighting, the position and illuminance value of the local lighting during dynamic testing must be indicated in the test record. During illuminance testing, it should be confirmed that all light sources are working normally. Otherwise, the condition of the light source must be recorded in detail, and attention should be paid to the projection of the tester and the reflection of clothing affecting the test results.

②The illuminance test should be conducted after testing the temperature value of the clean room (area) being tested. After the illumination testing instrument is turned on and preheated to stability, it can be calibrated according to the instructions and the corresponding testing range can be selected.

③The light receiving surface of the illuminance meter should be aligned with the corresponding horizontal plane of the test point as much as possible, and testing can only begin after confirming that the reading is stable.

④Sampling point arrangement for illuminance testing: The sampling points in any clean room (area) shall not be less than2In addition to being limited by the equipment in the clean room (area), the sampling points should be evenly distributed throughout the entire clean room (area), and the sampling points should be placed away from the wall1m(Small Room)0.5m）, press1~2mDistribution of spacing points. The spacing between each selected sampling point shall not exceed2mDo not deliberately select points under or avoid the light, at least sample1Next, on a plane, if the indoor workbench is used as the object surface, the test surface is defined as its surface0.05mThe horizontal plane.

Reference standardsGB 50591-2010Construction and Acceptance Standards for Cleanrooms

（10）Noise

In general, only detection is allowedASound level noise, if necessary, a sound level meter with an octave band analyzer can be used, according to the center frequency63、125、250、500、1000、2000、4000The8000HzOctave band detection, near the measuring point1mThere should be no reflectors inside. The minimum scale of the sound level meter should not be lower than0.2dB（A）.

The height of the measuring point from the ground1.1mThe area is15m2The following clean rooms can only measure the center of the room1Point,15m2The above clean rooms except for the center1Outside the point, the diagonal should be measured again4Point, each from the side wall1mThe measuring points are oriented towards each corner.

When it is a mixed flow clean room, the noise in the unidirectional flow area and non unidirectional flow area should be measured separately.

If possible, it is advisable to measure the background noise of the air conditioning purification system after it stops running, and the difference between indoor noise and background noise should be less than10dB（A）Correction should be made to the measured point values: difference（6~9）dB（A）Time reduction1dB（A）, difference（4~5）dB(A)

（11）Efficient filter leak detection photometer method

1The leak detection filter must have been tested for air volume, within the designed wind speed80%~120%Running between them.

2When there are multiple filters on the same air supply surface, it is advisable to use only exposed filters at a time, if structurally allowed1The method of measuring with a filter is used.

3When several or all filters must be exposed to aerosols at the same time, in order to achieve uniform mixing of all filters, it is advisable to introduce leak detection aerosols into the suction end of the fan or the branch pipe in front of these filters, and immediately measure the concentration on the upwind side directly in front of the tested filter.

4For university filters, when the leak detection instrument has a logarithmic scale, the aerosol concentration on the upwind side should exceed the minimum scale of the instrument104Twice. When the leak detection instrument has a linear scale, the aerosol concentration on the upwind side should reach（20~80）μg/LThe concentration is lower than20μg/LIt will reduce the sensitivity of leak detection, higher than80μg/LLong term testing can cause filter contamination and blockage. Leak detection instruments should have（0.001~100）μg/LThe measurement range.

5The standard transmittance for confirming local leakage of the filter using photometric leak detection method is0.01%When the sampling probe is aligned with a certain point of the air outlet of the tested filter and static detection is performed, if the measured transmittance is higher than0.01%It is considered as a leakage point.

Time reduction2dB(A), difference3dB(A)Time reduction3dB(A)The difference is less than3dB(A)The measured value is invalid.