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Basic knowledge of clean operation
1. Clean room (area): a room or area that requires environmental control for dust particles and microbial contamination. Its building structure, equipment and its use have the function of reducing the intervention, generation and retention of pollution sources in the area. Other relevant parameters such as temperature, humidity, pressure, etc. are controlled as required.
2. Purification: the process of removing pollutants in order to obtain the necessary cleanliness.
3. Air purification: the process of removing pollutants in the air to make the air clean.
4. Whole room air purification: a method of making the dust concentration in the air of the indoor working area reach the specified cleanliness level through technical measures such as air purification.
5. Local air purification: a method of making the concentration of suspended particles in the air of a specific local space in the indoor working area reach the specified air cleanliness level.
6. Particles: solid and liquid substances with a size of 0.001~1000um.
7. Suspended particles: airborne particles used for air cleanliness classification, solid and liquid particles with a size range of 0.1~5um
8. Cleanliness: the allowable statistical number of suspended particles greater than or equal to a certain particle size in a unit volume of air in a clean environment. The degree of cleanliness is distinguished by the number of certain particles in a unit volume of air.
(Figure 1: Sterile room)
9. Unidirectional flow (laminar flow): airflow with parallel streamlines in a single direction and consistent Wind speed on the cross section. It is divided into vertical unidirectional flow and horizontal unidirectional flow.
10. Non-unidirectional flow (turbulent flow): airflow with multiple path circulation characteristics or non-parallel airflow directions, which does not meet the definition of unidirectional flow.
11. Static test: a test conducted when the clean room (area) purification air conditioning system is in normal operation, the process equipment has been installed, and there are no production personnel in the clean room (area).
12. Dynamic test: a test conducted when the clean room (area) is in normal production.
13. Sterility: the absence of active organisms.
14. Sterilization: a method to achieve a sterile state.
15. Sterile API: API without live microorganisms.
16. Non-sterile API: API with live microorganisms that meet hygienic standards.
Air treatment measures for air purification system
1. There are many types of Air Filters.
2. Airflow organization and ventilation
To achieve a specific purpose, a certain air flow state and distribution is created indoors, which is usually called airflow organization.
2.1 The basic principles of airflow in clean rooms are.
Minimize eddy currents;
Make the airflow cover the work area as quickly as possible through the shortest process;
It is hoped that the airflow direction can be consistent with the gravity settling direction of dust, and that the backflow can effectively discharge indoor dust to the outside.
2.2 Airflow organization method:
The turbulent flow method mainly uses the dilution effect to evenly diffuse the dust generated by the indoor dust source and "dilute" it. Its principle is to meet the process and personal hygiene requirements, avoid eddy currents from rolling dust outside the work area into the work area, and reduce the chance of drug contamination. Generally, the form of up-sending and down-returning is adopted to make the airflow from top to bottom, consistent with the gravity direction of dust particles.
Suitable for 10000-300000 clean area laminar flow mode, refers to the airflow organization mode with parallel streamlines, single flow direction, and certain and uniform cross-sectional velocity. The airflow sent into the room fills the entire clean room cross-section, and it acts like a "piston" to press the dust generated indoors at any time to the leeward side, and then discharge the dust to the outside to achieve a cleanliness level of 100. Laminar flow modes are divided into vertical laminar flow and horizontal laminar flow. The airflow velocity requirements are greater than 0.25 m/s and 0.35 m/s respectively.
2.3 Air supply mode
Vertical laminar flow (100 level): top supply and bottom return
Horizontal mode (100 level): side supply and side return
Turbulent flow (10000 level): top supply and side return
Turbulent flow (100000~300000 level): top supply and side return, top supply and top return
Ventilation frequency of 10000 level clean room n≥25 times/h
Ventilation frequency of 10000 level clean room n≥15 times/h
Ventilation frequency of 300000 level clean room n≥12 times/h
(Figure 2: Clean room air purification system)
3. Pressure control
In order to maintain the cleanliness of the clean room from contamination by the adjacent room or contamination of the adjacent room, maintain an air pressure higher or lower than that of the adjacent room in the clean room. At the same time, in order to prevent external pollutants from penetrating into the clean room with air from the doors and windows or other gaps of the maintenance structure, and to prevent air from flowing from the low clean area to the high clean area when the door is opened, the clean room must maintain a positive static pressure difference or negative static pressure difference with the adjacent room or corridor.
3.1 Principle of pressure difference in clean rooms:
Clean rooms must maintain a certain positive pressure. The static pressure difference between clean rooms of different levels should be greater than 5Pa, and the static pressure difference between clean rooms (areas) and the outdoors should be greater than 10Pa. There should be a device to indicate the pressure difference, and the pressure difference must be recorded.
In areas with the same air cleanliness level, operating rooms with large dust production should maintain a relative negative pressure. Clean rooms (areas) with high air cleanliness level requirements generally require a relative positive pressure for adjacent clean rooms (areas) with low air levels.
Strong allergenic drugs such as penicillin and other areas that are prone to contamination should maintain a relative negative pressure.
3.2 Design principles for exhaust and return air in clean rooms:
If the purified air in clean rooms (areas) can be recycled, effective measures should be taken to avoid pollution and cross contamination. When clean areas with large dust production cannot avoid cross contamination after dust collection treatment, their air purification systems shall not use return air. Process equipment that produces dust and harmful gases in clean rooms should be equipped with local exhaust devices. Dust collection facilities should have devices to prevent air backflow.
4. Temperature and humidity
The temperature and relative humidity of the clean room (area) should be adapted to the requirements of the pharmaceutical production process. If there are no special requirements, the temperature of the clean room (area) of Class 100 and Class 10000 should be controlled at 20~24℃, and the relative humidity should be controlled at 45~60℃; the temperature of the clean room (area) of Class 100000 and Class 300000 should be controlled at 18~26℃, and the relative humidity is 45%~65%.
5. Sources of dust in the clean room
Air, human body, internal environment dust, equipment dust, and dust accumulation.
5.1 Air: Dust particles in the air contain microorganisms.
5.2 Human body: Clean room operators are the main source of dust.
5.3 Internal environment: Most of the dust generated by the decoration in the clean workshop comes from the ground (caused by friction with the ground when the operator moves).
5.4 Equipment dust: Equipment generates dust during operation.
5.5 Dust accumulation: caused by uneven distribution of purified air flow.
(Figure 3: Sources of dust in clean rooms)
6. Seven indicators for evaluating air purification system (HVAC)
6.1. Temperature and humidity;
6.2. Static pressure difference;
6.3. Air volume [air supply volume (ventilation times) fresh air volume];
6.4. Number of dust particles;
6.5. Microorganisms;
6.6. Noise;
6.7. Illumination.
(Figure 4: HVAC)
7. Clean environment monitoring methods
7.1 Determination of dust particle number: dust particle counter.
7.2. Determination of microorganisms: mainly two methods are sedimentation bacteria determination and floating bacteria determination.
7.3. Determination of air volume: anemometer determination.
7.4. Test status: there are two types of static test and dynamic test. Static test: no more than 2 people are allowed to test indoors.
7.5. The test report should indicate the state used during the test.
7.6. Test time:
The unidirectional flow test should start at least 10 minutes after the purified air system has been operating normally.
For non-unidirectional flow, the test should be started after the Clean air conditioning system has been operating normally for no less than 30 minutes.
Basic knowledge of clean room hygiene
1. Basic concepts
Supervision of production hygiene:
Layout of buildings and logistics design of materials and personnel Selection of materials for floors, walls, ceilings and equipment in the middle room Protective equipment and work clothes for personnel Hygiene procedures for personnel Cleaning and disinfection procedures for rooms and equipment Safety facilities; The special importance of hygiene work in the implementation of GMP in pharmaceutical companies The particularity of drugs determines the strictness of their quality.
Changes in drug quality caused by drug contamination.
(Figure 5: Clean room hygiene)
2. Hygiene management of pharmaceutical companies
Environmental hygiene
Personnel hygiene
Production process hygiene
2.1 Environmental hygiene
Garbage management
Lawn management
Three wastes treatment
Rat prevention
Insect prevention
2.2 Personnel hygiene
2.2.1 Personal health: New employees must undergo a physical examination and can only take up their posts after passing the examination. Pharmaceutical production personnel should have a health record, and production personnel who directly contact drugs should have a physical examination at least once a year, and can continue to take up their posts after passing the physical examination. If production staff find themselves feeling unwell during work, they should report to their supervisors and go to the hospital for examination and treatment. If they are found to have infectious diseases, mental illness, traumatic wounds, skin diseases and allergies, they should report to their supervisors in a timely manner and be transferred from their jobs. They must not continue to work directly in contact with drugs or related work. Staff who leave their jobs due to illness must hold a health certificate issued by a doctor before they can return to work after recovery.
2.2.2 Personal hygiene: Keep clean and hygienic, do not wear makeup or accessories; eating and smoking are prohibited in the production area, and non-production items and personal items shall not be stored.
2.2.3 Work clothes
The role of work clothes: First, prevent the contamination of drugs by dirt emitted by the human body, and second, avoid contamination or harm of drugs to personnel. The selection, style and wearing of work clothes should be adapted to the production operation and air cleanliness level requirements, and shall not be mixed. The texture of clean work clothes should be smooth, do not generate static electricity, and do not shed fibers and granular substances.
Work clothes used at different air cleanliness levels should be cleaned and sorted separately, and disinfected or sterilized when necessary. When washing and sterilizing work clothes, no additional particulate matter should be brought in.
2.2.4 Procedures for personnel entering and leaving the clean area
Washing hands:
Roll up sleeves and take off rings, watches or jewelry such as hands.
Wet your hands and use an appropriate amount of liquid soap or detergent.
Rubbing your hands together until a lot of foam is produced, clean each finger and between fingers, and apply foam to the wrist.
Remove grease from the palm of your hand and remove dirt from the nails (brush your nails with a brush if necessary).
Wash the foam and attached dirt, dandruff and bacteria in running water.
Carefully check all parts of your hands (back of hand, nails, palm, wrist), and rewash any dirt that may be retained. Dry your hands thoroughly
How to wear a mask:
Make sure the mask covers your mouth and nose.
Do not touch the mask with your hands when working, because the mask will become dirty after use.
Replace the mask after it becomes wet:
Do not put the replaced mask in your pocket, or put it directly in the designated container, then wash your hands and try to use a disposable mask.
When handling dust, dust masks should be used.
Self-restraint of personnel in the clean area
People working in the clean area must strictly abide by the management rules of the clean area.
The number of people entering and exiting the clean area should be as few as possible, and the range of motion should be reduced during the operation, and civilized operation should be carried out. Try to avoid unnecessary walking or moving to maintain the airflow, air volume and air pressure in the clean area to ensure the purification level of the clean area.
Do not go to other posts, close the door when entering and leaving the clean room, and close the door for production.
In short, the operation and actions of personnel working in the clean area must be self-restrained.
2.3 Production process hygiene
2.3.1 Material hygiene
Raw and auxiliary materials, inner packaging materials, containers and tools entering the clean area must be treated on the outer surface in the buffer room, or the outer skin must be removed, and effective disinfection measures must be taken before entering the clean area through the transfer window or airlock. The specific operating procedures for materials entering and leaving the clean area should be strictly implemented in accordance with regulations. The materials used in the clean area should be kept to a minimum, and no excess materials or materials unrelated to production should be stored in the clean area.
2.3.2 Equipment hygiene
The surface of equipment that directly contacts drugs should be smooth, flat, easy to clean and disinfect, corrosion-resistant, and should not undergo chemical changes with drugs or adsorb drugs. Lubricants, coolants, etc. used in the equipment must not cause contamination to drugs or equipment. Pipelines for transporting production materials for drugs should be installed to facilitate cleaning and disinfection to avoid cross-contamination between batches. Corresponding systems and procedures should be established for the cleaning, disinfection or sterilization of major equipment, and there should be operation, inspection acceptance or verification records. Equipment, containers, and pipelines used in clean areas must be rinsed with purified water after cleaning.
2.3.3 Production medium hygiene Drug production media mainly include: water, compressed air, steam, inert gas, etc. There are many media used in the drug production process, and most of the media have a process of production, transportation and use. In each process, there is a hidden opportunity for the medium itself to be contaminated. The hygiene and quality of the medium itself are unstable, which also causes fluctuations in drug quality.
2.3.4 Process Technology Hygiene
Some process technology parameters (such as temperature, time, pH, etc.) and process flow (such as filtration) may also cause product contamination. Suitable temperature is the condition for microbial reproduction. For example, fresh distilled water may be contaminated by microorganisms when it is naturally cooled to room temperature. Time influence: The main measure of contamination is the amount of bacteria, and time often plays an important role in this regard. It is necessary to control the time between each process, which is of great benefit to preventing drug contamination. The storage period and storage conditions of intermediate products in production should be specified.
Acidity (PH value) mainly affects the stability of drugs, but there is a certain optimal pH range for the growth of microorganisms, so PH value can also affect the growth rate of microorganisms, thereby affecting the hygiene of drugs.
Process flow hygiene
Whether the process flow is optimized plays an important role in whether the product can prevent microbial and dust contamination, drug mixing, etc.
2.3.5 Clearing management:
Clearing is to prevent contamination and cross-contamination between different batches, varieties, and specifications in production, as well as confusion. After each production stage of each batch of drugs is completed, the production operator should clear the site and write a clearing record.
The requirements for clearing the site are as follows:
There should be no dust or scale on the ground, no dust on doors and windows, indoor lighting, air ducts, surfaces, and switch box shells, and no debris related to production pipelines should be stored indoors.
The tools and containers used should be clean, free of foreign matter, and free of retained items from previous products.
There should be no drugs retained from previous production in the equipment, and no grease.
Non-special equipment, pipelines, containers, etc. should be cleaned or cleared every day or batch. When the same equipment continuously processes the same non-sterile product, its cleaning cycle should be carried out according to the equipment cleaning procedures.
When the packaging process changes the variety, all excess labels and packaging materials should be handled in accordance with regulations.
When changing varieties, difficult-to-clean items such as drying cloths and cloth bags should be replaced.
(Figure 6: Clean room standard operation)
3. Common knowledge of clean area operations
3.1 The number of people in the clean room (area) should be strictly controlled. Its staff (including maintenance and auxiliary personnel) should be regularly trained and assessed in basic knowledge of hygiene and microbiology, clean operations, etc.; temporary outsiders entering the clean room (area) should be guided and supervised. Personnel entering the clean room (area) are not allowed to wear makeup or accessories, and are not allowed to directly contact drugs with their hands. When it is unavoidable, they should be disinfected in time. Non-production items and personal sundries shall not be stored in the production area, and waste from production shall be handled in time.
3.2 The pools and floor drains in the clean room (area) shall not pollute the drugs, and floor drains shall not be installed in the 100-level clean room (area).
3.3 The transmission equipment used in the 10000-level clean room (area) shall not pass through areas with lower air cleanliness levels; buffer facilities must be installed between the clean room (area) and the non-clean room (area), and the direction of human and logistics must be reasonable.
3.4 The shoe changing room, dressing room, plastic washing room, and airlock room in the personnel purification room should be supplied with the same clean air as the clean room (area) air filtration system. The ventilation frequency increases gradually from outside to inside, but can be lower than the ventilation frequency of the clean room (area). The toilets in the personnel purification room should be continuously exhausted, and the indoor air static pressure value should be lower than the air static pressure value of the dressing room.
3.5 The insulation layer of the equipment in the clean room (area) should be flat, smooth, and no granular material should fall off.
3.6 Avoid using fragile, easy to fall off, and easy to grow utensils during the production process: measures should be taken to prevent the net from breaking and causing pollution when using it.
3.7 Sanitary tools that do not fall off, are easy to clean, and are easy to disinfect should be used in the clean room (area). Sanitary tools should be stored in designated places that will not cause pollution to the product department, and the use area should be limited.
3.8 The number of microorganisms and dust particles in the air of the clean room (area) should be monitored regularly, and the monitoring results should be recorded and archived. The number of dust particles, floating bacteria, or settling bacteria detected in the clean room (area) under static conditions should meet the regulations.
3.9 If the purified air in the clean room (area) can be recycled, effective measures should be taken to avoid pollution and cross-contamination.
The air purification system should be cleaned, repaired, maintained, and recorded as required.
