Drug production quality management standard (revised in 2010), mainly by reference to the eu GMP and combined with the actual situation of domestic revised, chapter 14, 313, at the same time also released the revised sterile drugs, pharmaceuticals, biological products and blood products and the appendix, the Chinese native medicine preparation requirements more refined, significantly improved the sterile preparations of cleanliness requirements. The new version of GMP for pharmaceutical products has proposed the clean zone A, B, C, D classification and the corresponding more stringent environmental suspended particles and microorganisms control requirements, the purpose of which is to prevent the production of pollution, confusion, cross contamination and human error. The issue and implementation of the new version of GMP has narrowed the gap between China and GMP management requirements, which will play an important role in promoting the process of China’s pharmaceutical industry, promoting the pharmaceutical industry to improve the quality management level, and ensuring the safety of people’s medication.
In order to achieve the corresponding indoor environment, in addition to controlling the dust content of clean room air, the number of bacteria and microorganisms should also be controlled. To clean indoor air, although after the early effect, in effect, high efficiency filter level 3, the most of the dust particles and adherent bacteria and microorganisms on the block in clean outdoors, but they still exist in the air conditioning system equipment, pipelines, tuyere and filter, once a suitable environment will be reproductive. There are also a small number of bacteria and microorganisms through all levels of filters into the clean room, become clean room microorganisms. If the clean room is not sterilized and sterilized, they will continue to multiply, destroy the quality of indoor air and environment, and affect the quality of products. Therefore, clean rooms should be sterilized and disinfected regularly.
Article 45 of Appendix 1 of the new GMP Aseptic Drugs states that, when necessary, fumigation can be used to reduce microbial contamination of the sanitary dead space in the clean area, and the residual level of the fumigant should be verified. This also puts forward higher requirements for the sterilization design of clean workshop under the new GMP. Traditional clean room disinfection (sterilization) methods in the pharmaceutical industry mainly include: disinfectant (formaldehyde fumigation) sterilization method, ozone disinfection (sterilization) method.
The traditional way to disinfect clean room gas is to fumigate the disinfectant through evaporation. The usual disinfectant is ethylene oxide, peracetic acid, formaldehyde solution, etc. Three important factors of formaldehyde bactericidal effect: increasing temperature, limiting relative humidity and improving penetration conditions. When the relative humidity is above 65% and the temperature is between 24 and 40°C, the disinfection effect is good.
However, formaldehyde fumigation has a series of disadvantages that can not be ignored:
Since each chemical fumigation sterilization time should be less, should not every day, so at present the most manufacturers use a month time big disinfection, and microbial pollution sources, people, objects, materials, such as outdoor fresh air everyday to be in and out of clean room, its into microbial cannot receive timely kill, there will be a microbial increases with time extension phenomenon.
Formaldehyde has a strong pungent odor, and it takes a long time to remove the residual odor after disinfection and sterilization, which is harmful to the body of production operators. As a highly toxic substance, formaldehyde has strong carcinogenic and carcinogenic effects. It is a recognized reaction source and one of the potential strong mutagens. Therefore, the application is limited, the European Union clearly stipulates that formaldehyde can not be used to sterilize clean rooms.
Formaldehyde fumigation will appear paraformaldehyde polymer (white powder), attached to the surface of the maintenance structure and equipment pipe in the clean room. Within a few days after disinfection, the number of suspended ions will increase, and the formaldehyde polymer will gradually depolymerize into formaldehyde, which is very harmful to the production operator.
The penetration of formaldehyde gas is poor, generally can not penetrate to the center of the bag or the inside of the catheter, it is not easy to accurately control the concentration of gas in the process of operation, and can not ensure that the factors affecting the sterilization ability of formaldehyde are effectively controlled.
The concentration of ozone disinfection according to the efficiency of ozone disinfection and the Ministry of Health issued “disinfection technical specifications (annual edition)” standard, for the plankton in the air, the concentration of ozone sterilization is, only need to open the ozone generator ~; For the settling bacteria on the object surface, the concentration of ozone sterilization is, and the opening time of the ozone generator needs to be adjusted to ~. Ambient conditions: ambient temperature ~ ℃; Relative humidity %; There is no outside strong airflow, strong sunlight or other thermal radiation in the room. During disinfection, close the discharge valves of the fresh air outlet and the return air outlet, so that the air in the whole clean area to be sterilized circulates through the air duct of the purification system, and the ozone generator begins to work.
The disadvantages of ozone disinfection are also very obvious, that is, high concentration is harmful to human body, poor compatibility with equipment surface and building materials, easy to make copper rust, rubber aging, and its sterilization environment requires relative humidity >60%, etc.
Vaporized hydrogen peroxide (VHP) sterilization technology is a technology that makes use of the advantages of hydrogen peroxide’s spore killing ability in gas state than in liquid state at room temperature to generate free hydroxyl group, which is used to attack cell components, including lipids, proteins and DNA, to achieve complete sterilization requirements. It is often used for sterilization of closed Spaces such as isolation rooms and isolators. Vaporized hydrogen peroxide (VHP) is sterilized, dry, fast, non-toxic and non-residual, with good material compatibility, including many metals and plastics, suitable for sterilization and disinfection of rooms, biosafety cabinets, transfer Windows, animal cage exchange stations, isolators and medical instruments and other surfaces. The biological purification time is short. According to the physical characteristics of the products to be treated, the biological sterilization time is 30-90min, which is effective for a wider range of microorganisms. The biological sterilization cycle does not produce toxic residues, and has little impact on other items (devices, electrical appliances, clean room wall panels, etc.). The disadvantage is that it is difficult to achieve complete vaporization of hydrogen peroxide, and the cost of complete vaporization of hydrogen peroxide is often expensive.
Germany PEA VHP vaporizing peroxide hydrogen generator adopt new techniques in three generations of dry flash, flash temperature control is not only stable, vaporization, completely produce hydrogen peroxide gas particle size is small, and in the different stages of sterilization can set different injection rate, in ensuring the sterilization effect (SAL can be controlled under 10-6) premise, improve material compatibility; Compared with the closed loop terminal of domestic equipment emitting hydrogen peroxide gas, PEA VHP vaporized hydrogen peroxide generator adopts open-loop and open gas circulation mode. The combination of gas distribution system makes hydrogen peroxide gas evenly distributed, effectively expands the disinfection and sterilization volume, and greatly improves the degradation speed. The mobile caster design makes the sterilization method more flexible and can be independently sterilized for different areas. Compared with the fixed air conditioning unit VHP sterilization method, it undoubtedly greatly reduces the cost and cost.