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Quality requirements for water for injection
Water for injection (WFI) has always been important in pharmaceutical waters in the various qualities of water used in the pharmaceutical industry. Water for injection is used to make various injections, such as vaccines that are in direct contact with the patient's blood, drip intravenous fluids and the like, and is used to clean the vials that package these products and the equipment that produces them. Therefore, it is required that there must be no pollutants in the water that are toxic or may interfere with the efficacy of the product.
The national pharmacopoeia clearly defines the water for injection, but the globalization of the pharmaceutical industry has made it necessary for companies around the world to manufacture products in the US market in accordance with the requirements of the US market, which makes the US Pharmacopoeia an international quality. standard. Table 1 lists the requirements for water for injection as defined by the United States Pharmacopoeia.
High-purity water easily absorbs CO2 in the atmosphere, then hydrolyzes to form hydrogencarbonate ions, and increases conductivity. The United States Pharmacopoeia proposes a method of compensating for the effect of CO2 on conductivity, but this method is very complicated, making online conductivity monitoring less convenient. Therefore, the conductivity required by the pharmaceutical manufacturer at the user end is lower than the conductivity of the water for injection, and the effect of CO2 is compensated. The conductivity of the user end is usually set at 0.1 to 0.5 μS/cm.
Total organic carbon is a measure of the amount of organic matter in water, most of which is humic acid and fulvic acid, as well as various derivatives produced during water treatment. Most of these materials are removed during the water purification process as the injected water is further purified by purified water. Therefore, the requirement for total organic carbon is relatively easy to achieve in water for injection.
Since bacteria can infect blood, the control of the number of bacteria is necessary. In addition, the water for injection must also be pyrogen-free water. When a pyrogen is injected into the blood, it can cause fever in the patient. Most of them are endotoxin, which is a large protein molecule produced by bacterial metabolism or cell breakdown. The main sources are Gram-negative bacteria such as Escherichia coli, Streptococcus faecalis, Clostridium welchii and Pseudomona sspp. The pyrogen-free requirement is an essential difference between water for injection and relatively pure water.
Production of water for injection
Certain pyrogen molecules can be decomposed by temperatures above 120 ° C, which ensures sterility in water. In previous Pharmacopoeia regulations, water for injection was produced by distillation. However, due to the moderate size of the endotoxin molecule, ultrafiltration and reverse osmosis with a molecular weight cutoff of 6000 daltons (with an effective molecular weight cutoff of approximately 200 Daltons) produce pyrogen-free water. Today's Pharmacopoeia allows the use of either of these two methods instead of distillation to produce water for injection. The US Pharmacopoeia allows the use of reverse osmosis, but current British and European Pharmacopoeia stipulate that water for injection must be produced by distillation. At present, pharmaceutical companies generally use distillation because this method is generally considered to be a "safer" method. However, the cost of the pharmaceutical distillation chamber is high, the source water for distillation must be purified water (purified water must meet the same chemical purity standards as water for injection) and clean steam is used as the heating medium, so they are expensive to operate. The membrane permeation system is low in capital and operating costs (so it has been proposed to use membranes to produce “pyrogen free water†for high-consumption, product-free applications such as bottle washing and reactor cleaning, and to produce water for distillation. Used only as a component of a product, there is still debate about its economy.)
Pharmaceutical facilities producing pharmaceutical products in the US market are subject to inspection by the US Food and Drug Administration (FDA), which is designed to ensure reasonable standards of implementation. For water for injection systems, this means meeting the standards of the United States Pharmacopoeia, but the US Pharmacopoeia currently does not specify the number of high-limit bacteria in Zui, providing only a guide value of 0.1 cfu/ml. Therefore, the FDA is concerned that the number of bacteria in the water for injection system is under control, that the number of bacteria needs to be low and relatively stable; and that the alert level and action level are appropriately set, and the measures that must be taken to achieve these levels are detailed. Based on.
Storage and distribution
Producing pyrogen-free water is a challenge, and ensuring that pyrogen-free water remains sterile during storage and distribution to the user is a challenge. This involves issues with system design and management. The pharmaceutical industry is often based on batch processes, which means that intermittent high-flow water supply is required to fill the reactor. (The continuous operation of the water treatment device brings good performance, and the system's large capacity and investment cost are mutually constrained. Therefore, the water treatment system is designed based on the continuous flow of the average flow. Filling the storage tank and then storing it The water tank is recirculated through the circulation distribution system.) Therefore, there is often a long period of time without water injection, during which time the water is stored in the storage tank and the recirculation system. If the water does not flow or is contaminated by microbes in the air, the bacteria may begin to grow, causing an increase in the total number of bacteria and pyrogens. Bacteria will multiply in stagnant areas and "dead ends", so careful piping design and continuous recirculation of water for injection through the annular mains are important prerequisites for storage and distribution systems. There are two options for storage and distribution systems: thermal and cold systems.
When a water for injection is produced by distillation, a heat distribution system is a suitable system. The steam heat exchanger is used to supplement the heat loss during storage and distribution, and the heat of distillation can be maintained at a temperature between 80 and 90 °C. At temperatures above 80 ° C, the activity of the bacteria is completely absent and the hot water remains almost sterile. Although chemical disasters do not occur, tanks and piping require insulation to protect personnel and reduce heat loss. In addition, cooling of the ends is required unless all hot water is used. Although this will increase the investment cost of the system, it significantly simplifies the management process.
If contamination is found in the hot water recirculation system, the system should be deeply disinfected. Deep disinfection often uses hot, clean steam. When the system is drained, clean steam is injected into the system. The steam is filled with the circulation system to raise the temperature and maintain the desired level at 121 °C. At this point, the low point and the outflow point are all open, and the gas trap is installed to ensure that the condensed water formed in the system is completely eliminated. After one hour, the injected water is reinjected into the circulation piping system.
Compared to the hot water injection cycle system, the cold water injection cycle system is less common, requiring careful monitoring and good management. Even with a bacteriostatic air discharge filter or a nitrogen seal in the storage tank, bacteria will inevitably enter the system, so routine monitoring is very important. As long as the temperature is kept low, bacterial growth can be reduced. Temperatures around 10 °C can inhibit most bacterial growth, so cold-circulation systems mostly operate at temperatures below 25 °C. Generally, the external cooling water is used to cool the refrigerant through the heat exchanger. Remove heat from the pump and the heat from the higher ambient temperature in the roof space. Since ultraviolet radiation generates free hydroxyl groups and oxidizes the pyrogens produced by them, the use of an ultraviolet sterilization device in a cold cycle system provides further sterilization protection.
Bacteria can breed, especially when the system is not used for a long time, this situation will have an impact on the level of pyrogens. When the number of bacteria reaches an unacceptable level, the system must be shut down and sterilized. Currently, most systems use an auto-sterilization design that can be sterilized at night using heat or ozone.
Heat sterilization is easy
A sterilization cycle is initiated to start the steam heat exchanger on the recycle mains. The circulating water is heated to about 85 ° C, usually at this temperature for one hour, and then cooled using a cooling water heat exchanger. The temperature sensor on the pipeline can detect and record the sterilization operation is completed, so this process can be certified by cGMP. Large systems require higher heat, and even if the pipes have insulation, the heating and cooling time will be longer; in order to protect personnel from injury, insulation is also necessary.
The only chemical that can be used for disinfection in water for injection systems is ozone. Compared to hot water or steam sterilization, this disinfectant has a shorter sterilization cycle and can be operated at room temperature. Because ozone can be destroyed by ultraviolet light, the various UV sterilization devices used in the system must be turned off before the dispensing system is sterilized. The membrane electrolysis cell injects ozone generated by the overflow of pure water electrolysis, and pure water containing ozone is injected into the storage tank and mixed with the circulating water. The ozone monitor ensures that the appropriate ozone concentration (typically 0.2 to 0.5 mg/L) is achieved at all points in the system, and the current concentration and duration are recorded for certification purposes. Once the sterilization process of the line is complete, the UV unit is activated to eliminate residual ozone in the distribution ring and automatically monitor and record the residual ozone concentration again.
Certification matters
The production of water for injection is generally considered to be a demanding process, and the water for injection system must meet the principles and principles of Good Manufacturing Practices (GMP). GMP rules, by themselves, are generally programmatic rather than illustrative, and some agencies have developed guidelines to help pharmaceutical manufacturers interpret regulatory requirements in areas such as engineering, sterilization, and validation. Regarding the water system, its influence is the ISPE Basic Baseline? Pharmaceutical Engineering Guide, which was written by the International Association of Pharmaceutical Engineers after consulting the Food and Drug Administration.
Traceable documents are a prerequisite for fulfilling GMP, and the standardization and installation integration of the device provides a number of important conveniences. Design standardization means that the design has been completed before the contract is launched, and that the project has a comprehensive and effective design certification material at the start of the project. Equally important to process and mechanical design is the design of the control system, which must be fully certified according to GAMP. Once again, the qualification (identification) of the standardized software designed has also been completed. A quality assurance certificate based on ISO 9001 or equivalent ensures that the design is implemented throughout the manufacturing and assembly process.
Integration allows the unit to be assembled, simulates the test run and provides complete factory acceptance test documentation. This will satisfy most installation and operational confirmations, which means that the equipment delivered to the site can be used for production as long as it is confirmed by production performance.
Obviously, the standardization theory has greatly reduced the engineering procedures for confirming procedures, and the integration also shows that because the device is manufactured under controlled conditions in the workshop, rather than being assembled on site, the installation time can be clearly shorten. All this helps to ensure the implementation of the fast track project and the interference caused by the small-scale site, so it saves time in the various stages of planning, design and installation of the contract.
All in all, such a combination, including the right treatment method – membrane method or distillation – is combined with an excellent system design. Whether it is hot water or cold water circulation systems, thermal disinfection or ozone disinfection; and excellent management will ensure that the standard of water for injection is always met. During the engineering design phase, the customer works closely with water treatment professionals and storage and distribution system designers. It is important to clearly share the responsibility for the performance of the project to the relevant responsible personnel, and the relationship between design and operation is very important. ELGA Process Water always ensures that their technicians and customers have a complete consensus before the system is designed. In this way, when the various components of the system are "buy in bulk", the expected long-term performance of the system is also achieved.
(Source: Source: China Pharmaceutical Technology Alliance)
How to ensure the quality of water for injection in the pharmaceutical industry
In the various quality waters used in the pharmaceutical industry, water for injection is important, so there are very strict requirements for the preparation, storage and distribution of water for injection, and must pass a series of certifications. This article will give a detailed introduction to the production and use of water for injection.