Features and design of clean pipelines in the pharmaceutical industry

Thread Content

As a highly common system element, pipeline systems are widely used in various chemical industries. However, each industry has its own specific characteristics and particularities; even within the pharmaceutical industry, it can be broadly divided into two types of processes: the API processing pipeline and the formulation processing pipeline. Regulatory requirements dictate that, in the field of pharmaceutical formulations, the media to be used are relatively common compared to those used in the field of active pharmaceutical ingredients. These mainly include softened water, purified water, water for injection, pure steam, and process compressed air. However, some of these media require high-temperature or low-temperature circulation, while others are subject to high pressures; special attention must be paid to these aspects. In the pharmaceutical formulation industry, the concept of \"clean quality\" must be given significant attention, particularly in terms of preventing and controlling microorganisms. It is essential to strictly comply with the relevant regulations regarding pipelines as stipulated in China’s GMP (Good Manufacturing Practice). If the product is an export item, it must also comply with the relevant requirements of the U.S. FDA and EU GMP. Below are some of the requirements and specifications set by Chinese GMP in this regard: Production equipment must not pose any hazard to drugs. The surfaces of equipment that come into direct contact with drugs should be smooth, flat, easy to clean or disinfect, and corrosion-resistant; they must not undergo chemical reactions with drugs, absorb drugs, or release substances that could affect product quality and cause harm. The design and installation of various pipes, lighting fixtures, air vents, and other utility systems should avoid creating areas that are difficult to clean; maintenance of such items should be carried out outside the clean area whenever possible. The design, installation, and maintenance of water treatment equipment and its delivery systems must ensure that the water used in pharmaceutical manufacturing meets the specified quality standards. Water treatment equipment must not be operated beyond its designed capacity. The materials used for purified water and water for injection storage tanks and delivery pipelines must be non-toxic and corrosion-resistant; the ventilation openings of the storage tanks should be equipped with hydrophobic sterilizing filters that do not release fibers; the design and installation of the pipelines should avoid dead corners and dead ends. The preparation, storage, and distribution of purified water and water for injection should prevent the growth of microorganisms; for example, water for injection can be kept at a temperature above 70°C through continuous circulation. The requirements and descriptions above represent the general principles for clean pipelines; it is essential to adhere to these principles from the outset of design in order to keep the operation of the clean utility systems in pharmaceutical systems under control. The following will provide a brief overview of some characteristics of clean pipes. Selection of materials for clean pipes, fittings, valves, and gaskets must comply with Chinese GMP requirements: “Production equipment shall not pose any harm to pharmaceuticals; it shall not undergo chemical reactions with pharmaceuticals, adsorb them, or release any substances into them, as this could affect product quality and cause harm.” ”When selecting the material for clean pipelines, the following considerations are primarily taken into account: The choice of materials for clean pipeline fittings and valves. Generally speaking, there is not much flexibility in selecting materials for such fittings and valves; in most cases, austenitic stainless steel is the most widely used material, suitable for various applications in the pharmaceutical industry. In these stainless steel compositions, different elements play distinct roles. A lower carbon content facilitates argon arc welding, while a higher nickel-chromium content helps to prevent corrosion. A higher nickel content also improves the ductility of stainless steel pipes, and an appropriate amount of molybdenum further protects against corrosion caused by chlorine. Taking all the above factors and cost considerations into account, 316L is the most suitable material for pharmaceutical clean pipelines. In addition, other materials can also be used, such as 316, 904L, 316Ti, etc., but each of them has certain limitations. The main consideration in material selection is rust prevention, with the aim of minimizing the likelihood of rust forming within the pipes. If a fluid of uncertain properties is to be transported through a pipeline, corrosion testing is a good method that can help designers select the appropriate material. The piping system also includes other components such as fittings, valves, and gaskets; the fittings and valves are made of the same material as the pipes. Firstly, it provides better corrosion resistance, and secondly, it prevents the occurrence of electrochemical corrosion. Selection of connection sealing components: Gaskets, as important connection sealing components for clean pipelines, are available in materials such as EPDM, PTFE, FPM, and silicone. The selection criteria largely depend on factors such as temperature, pressure, and fluid corrosiveness. Materials such as EPDM find it difficult to withstand operating conditions above 100°C for long periods of time; therefore, they are used more often in systems with lower temperatures. In high-temperature systems, especially steam systems, it is preferred to use heat-resistant materials such as PTFE or silicone gaskets. In actual production processes, it has indeed been observed that in some places, EPDM gaskets that are not resistant to high temperatures are used in clean steam piping systems, resulting in the aging and damage of these gaskets and thus contamination of the pipes. Therefore, special attention must be paid to this issue when selecting gaskets for high-temperature systems. If there’s no other choice, be sure to pay special attention to the usage time. Based on experience, it is generally acceptable for EPDM gaskets used in pharmaceutical plant clean steam systems to last no more than 1 year. Connection methods for clean pipelines: In clean pipelines, the way in which pipes are connected is of great importance. If the connections result in the formation of stagnant water, this will greatly violate the GMP requirements regarding clean pipelines. Welding is the best method for connecting clean pipes, and welding should be used as much as possible when designing and constructing pipelines. Welding of clean pipes must be carried out using TIG welding; the welding process requires strict protection with argon gas, and the oxygen content must be monitored during testing to ensure that the metal does not get oxidized into iron oxides due to oxygen at high temperatures. The standards used for welded fittings should be unified, such as ASME BPE or DIN, to prevent steps from forming inside the fittings. If possible, using automatic welding machines for welding tasks can ensure consistency in welding parameters such as electrode movement speed, welding current, and pulses. The general inspection requirement for automatically welded joints is 20% endoscopic inspection. In some cases, when automatic welding machines cannot be used, manual welding is the only option; generally, a 100% endoscopic inspection is required after manual welding. Clamp connection: This type of connection is widely used in the pharmaceutical industry. The sealing effect provided by gaskets helps to significantly reduce the likelihood of water accumulation, ensures more even distribution of forces, allows for long-term use, and is easy to disassemble. It corresponds to the connection method most frequently used when frequent disassembly is required, as well as when considering maintenance needs. Sanitary structure flanges are sometimes also used for connecting clean pipes, generally for pipes larger than 4˝, but they are not used very frequently; threaded connections are not used in clean pipe systems. Branch design in pharmaceutical clean pipeline systems: During the pipeline design process, it is inevitable that branches will be needed. If the valves on these branches are closed, then stagnant water will form between the branch and the main pipeline. During the design process, it is essential to minimize this distance as much as possible, ensuring that the valves on the branch lines are as close as possible to those on the main line. Although various regulations, terms, and even measurement methods regarding branch pipe design differ, none of these current approaches are mandated by \"laws and regulations\"; they are merely engineering recommendations and standards. The more formal guidelines currently in use include: the ISPE Guidelines for Water and Pure Steam from 2001, which stipulate that the length L from the outer wall of the main pipe to the dead end of the branch pipe or the valve sealing point should be ≤ 3 times the diameter D of the branch pipe (3D); ASME BPE guidelines from 2009, which require that the length L from the inner wall of the main pipe to the dead end of the branch pipe or the valve sealing point be ≤ 2 times the diameter D of the branch pipe; the U.S. guidelines for high-purity water testing from 1993, which specify that the length L measured from the center of the main pipe to the dead end of the branch pipe or the valve sealing point should be ≤ 6 times the diameter D of the branch pipe (6D); and WHO guidelines, which state that the length L from the outer wall of the main pipe to the dead end of the branch pipe or the valve sealing point should be ≤ 1.5 times the diameter D of the branch pipe. In daily design and construction processes, the 3D principles of ISPE are widely adopted in China, while the 6D principles are also used in the pharmaceutical industry. However, even if nD is not met, it is generally acceptable provided that it has been verified that the impact on water quality remains within limits. Requirements for self-drainage of clean pipelines: To prevent the risk of microbial growth, in the design of pharmaceutical clean pipeline systems, it is essential to ensure that water or other fluids within the system can be completely drained when the system is emptied. Therefore, maintaining a certain slope in clean piping systems is a necessary engineering requirement. In the actual installation process, various different installation methods are involved, each requiring a distinct approach. Piping slope installation type: During the design process, it is essential to consider the drainability of the system, especially for horizontal pipes. Under normal circumstances, the slope from horizontal pipes to the designed drainage point should be at least 0.5%. Different pipe layouts employ different slope installation methods in order to ensure good self-drainage capabilities. Similarly, during the installation of instruments, consideration should also be given to the system’s self-drainage function, as well as the selection of valves and their installation angles in clean pipeline systems. Valves in such systems have specific requirements, with an effort to avoid the formation of stagnant water. Among various valves, the diaphragm valve is the most commonly used. Thanks to its special design, the medium flowing through the pipe never comes into contact with any other pipe components outside the gasket at all, thus maintaining a clean environment. For this reason, it is most widely used in the pharmaceutical industry. During the installation of diaphragm valves, the valve’s self-drainage function must also be taken into account, which means ensuring a certain installation angle for the valve. The pipe roughness of clean pipes: The internal roughness of pipes also plays a very important role in stainless steel pipes used in the pharmaceutical industry. Firstly, if the inner surface of the pipe is very rough, it is quite likely that stagnant water will occur in the uneven areas of the pipe. This uneven surface can therefore very likely become a habitat for bacteria; in severe cases, biofilms may form, leading to contamination of the products or water used in pharmaceutical production. Secondly, the rough inner surface of stainless steel pipes can also likely lead to corrosion on the pipe’s inner wall. Because still water in the uneven areas on the inner wall of the pipes is likely to contain a certain concentration of chloride ions, and the presence of these chloride ions reacts with the chromium elements in stainless steel. And this reaction will **accelerate the corrosion of stainless steel and lower its corrosion potential. During the design process, it is necessary to determine the appropriate process to ensure the roughness of the inner wall of the pipeline. The pipe contact surfaces for pharmaceutical water or products must undergo cold rolling, passivation, mechanical polishing, or electro-polishing to ensure that the roughness of the inner wall of the pipes is less than 1μm. Summary: The above briefly introduces some characteristics of clean pipelines in the pharmaceutical industry. Among them, the control and detection of stagnant water blind pipes, as well as the strict requirements regarding the inner wall roughness of pipes, are all aimed at controlling microorganisms in the pipes. It can be said that the control and prevention of microorganisms should receive special attention during the design and construction of clean pipelines; this is a distinct feature compared to other industries. Any oversight or negligence could potentially affect the quality of the drugs produced, so it is essential to take preventive measures from the very beginning.