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Part 1 Overall Analysis Of Purified Water System
The purified water system usually consists of two parts: preparation and distribution systems. The function of the preparation system is to treat raw water (usually tap water) into water that meets the standards of the Pharmacopoeia through multiple process steps. The function of the distribution system is to deliver pharmacopoeia-compliant water to the various points of use through distribution pumps. The microbial control of the entire water system not only requires construction, installation and operation to be carried out in accordance with GMP (Good Manufacturing Practice) regulations, ASME/ISPE (American Society of Mechanical Engineers/International Society of Pharmaceutical Engineering) guidelines, etc., but also requires that the water system design stage Consideration must be given to microbiological control.
Part 2 Preparation System Microbial Control
The goal of the preparation system is to remove the microorganisms in the raw water. From the design point of view, it is necessary to gradually remove the microorganisms through different process steps instead of just one process step. At the same time, it is necessary to avoid the rapid growth of its own microorganisms as much as possible.
In the preparation system, the multimedia filter is used for preliminary removal of impurities such as suspended solids, large particles and colloids; the softener is mainly used to reduce the concentration of Ca2+ and Mg2+ plasma, thereby reducing the hardness of water; Chlorine and reduction of TOC (Total Organic Carbon) – Due to the huge surface area of activated carbon, it can adsorb and reduce TOC very well, but while adsorbing organic matter, this also causes activated carbon filters to become a natural breeding ground for microbial growth. Since the multi-media filter, softener and activated carbon filter do not have the ability to remove microorganisms, they will cause the rapid growth of microorganisms, which requires pharmaceutical companies to regularly pasteurize the multi-media filter, softener and activated carbon filter. Because activated carbon filters are more likely to cause the growth of microorganisms, some companies even have to use industrial steam to ensure the effect of microorganisms.
Based on the concept of “Quality by Design”, we should use UF (ultrafiltration) membranes instead of multimedia filters and activated carbon, replace softeners with electromagnetic descaling instruments, and replace activated carbon with medium-pressure UV (ultraviolet) lamps to remove residual chlorine .
UF membrane belongs to a kind of membrane filtration technology, which adopts cross-flow filtration method. UF membrane not only has a certain ability to remove suspended solids, large particles and colloids, but also can effectively intercept and remove viruses and microorganisms. In order to prevent fouling on the surface of the membrane filament, the UF membrane needs to be washed with air and water regularly. Adding sodium hypochlorite during the air-water washing process can kill and control the microorganisms on the surface of the membrane filament.
The electromagnetic descaling instrument applies a certain magnetic field to the water through the electromagnetic induction coil to change the characteristics of the water and dissolved ions, thereby achieving the purpose of reducing the hardness of the water. While reducing water hardness, the magnetic field energy can also control the reproduction and survival of microorganisms in raw water.
The main function of the UV lamp is to remove residual chlorine and protect the RO membrane in the subsequent process from oxidation. However, UV light can also destroy RNA (ribonucleic acid) and DNA (deoxyribonucleic acid) in microorganisms while removing residual chlorine, thereby destroying the metabolism, genetics and mutation functions of cells, and eventually leading to the death of cell structures. The irradiation dose recommended by ISPE to remove residual chlorine with UV lamp is more than 20 times the disinfection dose, so when using UV lamp to remove residual chlorine, it can also kill microorganisms, and the endotoxin produced after killing can be eliminated by subsequent processes. The RO membrane effectively intercepts and removes.
This paper recommends the use of medium-pressure UV lamps, because medium-pressure UV lamps have a major advantage over low-pressure UV lamps: the microbial cells after irradiation cannot be repaired.
After using UF membrane instead of multi-media filter and activated carbon, replacing softener with electromagnetic descaling instrument, and replacing activated carbon with medium-pressure UV lamp, the microorganisms produced in the whole preparation process can be gradually removed. At this time, supplemented by periodic pasteurization or chemical disinfection of RO membrane and EDI equipment, the microorganisms in the entire preparation system can be well controlled, and the number of microorganisms in the water produced can be much lower than the microorganisms in the Pharmacopoeia index.
There is also a special point to be made here. Usually, when the purified water preparation system is in standby, a small cycle will be set to prevent the rapid growth of microorganisms. In the small circulation state, the pipeline still cannot reach the turbulent state, so it is best to cancel the small circulation in the design, and use other means to ensure that the preparation system is always in a normal water production state.
Part 3 Distribution System Microbiological Control
Before discussing microbial control in distribution systems, we need to understand the laws of microbial growth. A typical microbial growth curve includes four periods: lag phase, logarithmic phase, stable phase, and decline phase.
- Lag Period
During this period, the growth rate constant of microorganisms is 0, the bacteria are thick, the RNA content increases, the metabolic activity is strong, and the resistance to adverse environments decreases.
- Log Phase
This period is the period with the fastest growth rate of microorganisms. During this period, the metabolism of microorganisms is vigorous, the enzyme system is active, the number of viable bacteria is roughly close to the total number of bacteria, and the chemical composition and physical and chemical properties of cells are basically the same.
- Stable Period
This period is the period when the number of living bacteria remains relatively stable, the total number of bacteria reaches the highest level, and the accumulation of cell metabolites reaches the highest peak. The consumption of microbial nutrients is large, and the ratio of nutrients is out of balance.
- Decay Period
During this period, the rate of bacterial death is greater than the rate of new growth, the entire population undergoes negative growth, cells begin to deform, cells die and autolysis occurs.
Purified water is not a sterile material, but it does not contain nutrients, which is not conducive to the growth of microorganisms. According to the microbial control curve shown in Figure 6, the distribution system must have on-line disinfection measures and periodic disinfection measures. On-line disinfection is to suppress the microorganisms in the lag phase, and when the system microorganisms have a tendency to develop to the logarithmic phase, it needs to be carried out. Periodic offline pasteurization. Therefore, the disinfection of the purified water distribution system is recommended to adopt the method of online medium-pressure UV lamp disinfection + periodic offline pasteurization.
In the distribution system, if the control of microorganisms and online disinfection can be done well, and the microorganisms can always be suppressed in the lagging period, then the offline disinfection cycle interval of the distribution system can be extended. Conversely, if there is no means to reduce the microbial load in the distribution system, and there is no online disinfection configuration, then the microorganisms in the system will soon enter the logarithmic phase, and the offline pasteurization cycle will naturally be shortened accordingly. This is why this article recommends the use of online medium-pressure UV lamp disinfection + periodic offline pasteurization in the purified water distribution system.
Part 4 Conclusion
Doing a good job of microbial control in the entire water system not only requires pharmaceutical companies to refer to GMP regulations, ASME/ISPE guidelines and other requirements during system construction, installation and operation, but also requires companies to consider adopting multiple processes in the preparation system design process to gradually control microorganisms. Elimination, in the design of the distribution system, consider the use of online disinfection measures, supplemented by periodic pasteurization. Only in this way can microorganisms be well controlled and the disinfection cycle of the system can be extended to a certain extent. This article mainly provides some insights from the design concept of purified water, hoping to provide a useful reference for pharmaceutical companies to solve microbial control.