Medical clean room online environmental monitoring

Talking about the dynamic monitoring of A/B clean area
1 Overview Sterile drugs refer to the preparations and APIs listed in the drug standards for sterility tests, including injections, ophthalmic preparations, sterile ointments and sterile suspensions. In the process of drug production, the environment is an important factor affecting the quality of drugs. The production environment and personnel behavior directly determine the quality of drugs, especially the production process of sterile drugs.

2 Significance and role of implementing dynamic monitoring In the A/B clean area, the implementation of dynamic monitoring provides the necessary basis for personnel behavior evaluation and release of zui final products, so as to timely identify the problems and timely take effective measures to solve them. The problem is to prevent further expansion of the adverse effects, and at the same time provide a basis for further improvement of air balance, personnel behavior and room disinfection methods. In addition, in order to determine whether the clean room has reached the specified cleanliness, and to provide continuous and stable protection for production, it is an effective tool for evaluating the control of the production environment, and is the primary condition for the release of sterile drugs. 3 Dynamic monitoring of projects and standards

3.1 Monitoring items Before the production operation, the temperature, humidity and pressure difference in the area should be inspected and controlled; in the production process, the settled bacteria, floating bacteria, suspended particles and wind speed should be monitored; after the key operations are completed, Monitor the surface of the facility, equipment, and personnel hygiene. At the same time, the isolation gloves are tested before and after the start of production.

3.2 Temperature and humidity monitoring There is no specific requirement in the 2010 version of GMP. However, the author believes that this is not a reduction of the corresponding standard, but an increase in the corresponding standard, which requires the comfort of each enterprise from the product process, equipment, and personnel. Effective control of temperature and humidity in terms of sex and microbial living environment. For example, medium-temperature microorganisms are suitable for growth at 25 to 30 °C; wet-type microorganisms grow and reproduce in an environment with a humidity of 70% to 90%. Therefore, it is generally necessary to avoid this temperature and humidity range. At the same time, the temperature and humidity are too high or too low, which has a great impact on the comfort of the human body and the working mood of the personnel. It will seriously affect the operation behavior of the personnel in the A/B area and cannot effectively guarantee the safety of the product. Sex. Under normal circumstances, the temperature of the living environment of the sterile preparation should be controlled at 18 ~ 24 °C, and the humidity should be controlled at 45% ~ 65%.

3.3 Relative differential pressure monitoring The 2010 version of GMP stipulates that the difference between the static cleanliness of cleanliness grades and between clean and non-clean areas should be greater than 10 Pa, and should be equipped with means to indicate differential pressure; The production area should maintain a relative negative pressure with adjacent chambers (zones); an appropriate pressure gradient should be maintained between different functional areas (operating rooms) of the same cleanliness level. At present, the commonly used differential pressure gauge range is between 0 and 60 Pa, and the differential pressure differential gauge range is generally selected between -30 and 30 Pa. Therefore, in the daily production process, the instrument or the instrument itself should be verified or The correction situation strengthens supervision and management, because the pressure difference can increase the abnormal alarm situation. However, in order to avoid the alarm caused by normal operation (such as opening the door), the alarm delay device can be appropriately added. The specific delay time can be verified according to the time required for different personnel to open the door, enter or transfer the material, and close the door.

3.4 Particle and microbial monitoring The design of the clean area must meet the corresponding cleanliness requirements to achieve [static" and [dynamic" standards. At the same time, the area should also dynamically monitor microbes (floating bacteria, sedimentation bacteria, surface microbes). Microorganisms mainly include viruses, rickettsia, bacteria, fungi and protozoa, but mainly related to clean rooms are bacteria and fungi. Because the bacteria can not survive alone, it is generally attached to the dust particles. Therefore, it can block the dust particles through the initial effect, medium efficiency, and (sub)high-efficiency filtration of the air conditioner, and at the same time, the bacteria can be blocked. For aseptic areas, microbiological testing is more important, but the period of direct detection is long, so particle levels can be used to indirectly measure their specific conditions. That is to say, the detection of these two aspects can evaluate the damage degree and hygienic condition of the aseptic production process environment, and provide data support for the release of the Zui final product.

4 Dynamic monitoring methods and points of attention

4.1 Suspended Particles At present, there are two methods for measuring suspended particles: microscopy and automatic particle counting. The instruments used for airborne particle monitoring in clean areas are mostly light scattering particle counters and laser particle counters. Based on the actual situation, it is recommended to use a continuous monitoring system to detect airborne particles in the Class A area. The online monitoring system can feedback the monitoring information in real time, so that the monitoring personnel can promptly propose a solution to the problem. For example, the operator is reminded to reduce the range of motion and provide a basis for production process control such as environmental cleaning, disinfection, and shutdown waiting. At the same time, a complete set of operation, testing and replacement procedures should be established for the daily inspection and maintenance of air-conditioning filters. Only by doing so can we effectively control the risks that exist there.

4.2 Planktonic bacteria The planktonic sampler is often used to monitor the planktonic sampler in the impact method, and the air is extracted through the porous cover, while the microorganisms in the gas stream impinge on the surface of the agar medium attached to the standard culture dish. Usually, when measuring the floating bacteria, the sampling amount of each sampling point should not be less than 1 m3, and in the production process, the sampler can be set, and the whole process of production can be monitored by the gap method of sampling, waiting, and resampling. In addition, the floating bacteria sampler also has sampling methods such as mesh impingement, surface vacuum sampling, centrifugal, filtering and liquid impact.

4.3 Settling bacteria Settlement bacteria are collected by living organisms that have been collected in a culture dish by exposure, and cultured, propagated, and counted. Petri dishes measured by sedimentation bacteria should be placed in a representative place and where the airflow disturbance is small. The specific sampling method and culture method is that after the culture dish is placed at a position close to the operation height, the outer cover is opened and the buckle is placed to expose the surface of the medium. In the static monitoring, the culture dish should be placed for not less than 30 minutes before the cover is collected. In the dynamic monitoring, the exposure time should be verified according to the sedimentation disc itself and the environment. The exposure time of the single sedimentation disc can be Less than 4 h, but no more than 4 h. In the same position, multiple sedimentation discs can be used to continuously monitor and accumulate counts, and then collect. Yeasts and molds are usually counted after incubation for 5-7 days at 20-25 °C, while aerobic bacteria usually range from 30 to 35 °C. The conditions were counted after 48 to 72 hours of culture.
The sedimentation disc is widely used in the environmental detection of clean areas because of its advantages of low cost, light weight and less damage to the air environment. However, when using a sedimentation disc, the exposure time of the sedimentation disc should be confirmed (remember the opening and ending time of the plate) to ensure that the exposed medium does not affect the normal growth of microorganisms due to water loss and the like. At present, many manufacturers of petri dishes are self-contained by the factory, and the culture vessels that are not sealed are not strong. In the production process, the transport will cause pollution to the petri dishes themselves, and the results will be false positive. Therefore, it is recommended to use the blank control of the culture dish itself or purchase a well-sealed culture dish in the production process to improve the credibility of the test results.

4.4 Microbiological testing of surface of objects Surface microbiological testing of objects can determine the degree of contamination of microorganisms on the surface of objects (including overalls). Under normal circumstances, you can use the cotton swab indirect sampling, culture, direct contact sampling and surface washing methods. When using the direct contact method, the contact disc used should be placed at room temperature and used.

4.4.1 Sampling method for swab wiping surface The sampling area of the swab wiping surface sampling method is generally 25 cm2. The surface of the human body should at least include finger prints, head, mask, shoulder, forearm, wrist and leg. The indirect sampling of the cotton swab is suitable for irregular surfaces. When sampling, hold the swab handle with the hand and contact the sampling surface at an angle of 30°. Use a slow S- or Z-type swab and swab the cotton swab. If the swab head is a calcium alginate material, use a dilute hydrochloric acid solution as a diluent (such as a 1% sodium citrate solution) to allow the swab head to dissolve completely.

4.4.2 Direct contact method The direct contact method is to directly contact the surface of the object to be sampled, and the contact time is generally about 10 s. After the cultivation, colonies will grow. Because this method is easy to operate and can be quantified, it is widely used. However, this test is only suitable for flat, smooth surfaces and is usually sampled before clearing or filling. After sampling, the sampled surface is wiped with a gauze having 75% by mass of ethanol to remove the residue. The sampled dish after sampling and placed in the incubator is placed in an incubator for cultivation. The parameters of the incubator are generally set at 30 to 35 ° C, and counted after 72 hours of culture.

4.4.3 Surface rinsing method The surface rinsing method is suitable for monitoring the microbial bacteria content in the inner surface of a large area, including equipment rails and water storage tanks. Rinse the surface with a volume of sterile water, collect the rinse water, and calculate the number of microorganisms by membrane filtration.

4.5 Wind speed test detects the wind speed in the A-class zone during the production process, so that the wind speed of the production environment meets the guiding value (0.36~0.54 m/s). At the same time, it can also judge whether the laminar flow is open, whether it is running normally, whether it is blocked or leaked. Make the production environment meet the requirements. At present, since the installed isolator has good airtightness, the laminar wind speed can be appropriately reduced by corresponding verification. Some literatures indicate that the A-zone can choose the flow pattern of positive pressure sterile turbulence, and it is not necessary to choose the laminar flow pattern.

4.6 Detection of Isolating Operator Gloves At present, the integrity test is generally used when testing gloves, and a certain pressure is applied to the inside. The pressure drop value is within the acceptable range within the specified time. In addition, it is also possible to increase the visual inspection procedure of the gloves before and after the production of each shift. The inspection cycle should be verified based on factors such as product characteristics, equipment and shift schedule.

5 Daily monitoring of sampling points and sampling frequency The location of the key points of the zui is not necessarily applicable as a sampling point. Therefore, the probability that environmental monitoring will increase the risk of product contamination must be considered. For example, the sampling point of suspended particles is generally placed at a position of 0.8 to 1.5 m from the ground. Try to avoid sampling near the return air inlet, and the tester should stand on the downwind side of the sampling port. The sampling points and sampling quantities in the clean area monitoring can be less than the sampling points and sampling quantities when the clean area level is confirmed. The sampling points are verified by verification, and they are analyzed by risk analysis and monitoring results (at least 6 months or more) The operational data is used as the basis for the analysis). The frequency of monitoring is also a subject worth pondering. If the frequency of monitoring is insufficient, it will not reflect the problems that exist in it. The frequency of monitoring is too high, which is not conducive to resource optimization. Therefore, the determination of the frequency of monitoring generally uses the risk value distribution (RNR), which is the product of the severity of the occurrence of the risk (SEV) and the probability of occurrence of the risk (OCC). Different monitoring frequencies are determined according to the magnitude of the risk value, and practical measures are also taken to reduce the risks.

6 daily video surveillance

As a production place for pharmaceutical companies, the clean area has strict regulations and requirements for the environment and personnel. The monitoring of clean workshops is particularly important. The environmental monitoring system (EMS) is now used to strictly manage and control the clean area environment. The management mode of realizing remote off-site supervision in clean areas has become an inevitable choice. The embedded dedicated camera in the clean area is selected to realize remote off-site supervision of the clean area. The embedded special camera in the clean area is a special camera for real-time monitoring of important equipment/key positions in clean areas and clean rooms. The design of pure flat board adopts the installation method of embedded Color Steel Plate. After installation, the camera panel and color steel plate are installed. The wall is flush, realizing the zero sanitary corner of the clean area camera, easy to clean, and cleaning the wall while cleaning the camera. It adopts standard POE power supply mode, which can be quickly and multi-pointed and controlled, and is compatible with mainstream video systems.

7 General over-standard processing methods and report printing In the daily monitoring process, if the monitoring data is biased, its data will be higher than the set limit. Therefore, it is necessary to investigate what happened through CAPA (prevention and corrective measures) and how to prevent it. This problem occurs again, and the deviation and its follow-up measures must be recorded accordingly. Therefore, we must analyze problems from the six aspects of people, machines, materials, methods, loops, and surveys, use risk assessment tools to check risk points, find out the causes, and formulate practical measures to solve problems. At the same time, we can also make necessary assessments. And assessment work to solve the problem fundamentally. During the daily monitoring process, each batch of reports is printed and attached to the production records of the corresponding batch. Production time can generally be divided into four stages: preparation, self-purification, production and clearance. However, the author believes that the time for printing the report should include the self-cleaning time and production time of the environment, and it should be noted to explain the monitoring of abnormal and excessive results, thus ensuring product production. Traceability of the situation.

8 Conclusion With the increase of drug supervision and market requirements, pharmaceutical manufacturers must strictly control the whole process of production, especially the whole process of aseptic drug production. The application of automation technology makes the unmanned operation of the pharmaceutical production line gradually become possible; the use of sterile isolators makes it possible to operate unmanned key processes. However, at present, there are still some shortcomings in the use of domestic isolation operators. For example, online monitoring of the process of placing and removing culture dishes, difficulty in performing online replacement of gloves, and lack of emergency treatment measures when there is a leak in the system. To address these issues, more systematic research is needed. At the same time, the application dynamic monitoring system can provide data and alarm information in real time, facilitate the timely control of the production process, and take effective measures to solve the problems in the production process. In addition, the application of online monitoring system can reduce the external intervention of the staff, reduce the pollution caused to the production environment, ensure the quality of the product, and maintain the life safety of the patient.