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Part 1 Overview A good piping process is a fundamental requirement for the successful operation of all solid dosage form systems or biologic product system installations. All systems consist of process equipment and pipelines, which must be capable of achieving thorough waste removal, complete cleaning, and full sterilization in order to meet the requirements for manufacturing pharmaceutical products. Over the past decade, previous projects have demonstrated numerous advantages, reducing delays and improving the efficiency of process pipeline installation. Take the implementation of the three granulation production line projects at AstraZeneca Pharmaceuticals (China) Co., Ltd. as an example. The production line involves the installation and connection of utility media such as nitrogen piping systems, CIP in-line cleaning pipes, WFI water washing pipes, drain pipes, purified water pipes, steam pipes for cleaning and sanitizing the product kettle, steam condensate pipes, and compressed air pipes. This project must be planned in advance by the owner, with coordinated efforts among relevant personnel such as design engineers, project managers, installation managers, third-party QA supervisors, and verification teams to complete it. Before starting construction, the owner must have a very clear understanding of the required systems and their functions. Computer simulations can be used, along with the involvement of engineers from various fields and different suppliers, to help clarify all the details involved in the work. Mechanical installation contractors have **improved their manufacturing techniques for pipeline installation. Now they have better production processes and smaller welding \"cuts,\" and these relevant documentation records can be submitted to the FDA for certification, making their work more efficient. To a certain extent, this is attributed to the widespread use of automatic welding and the installation contractors’ understanding of SOP standard operating procedures. These written SOP procedures require that every welder follow the same steps, handling the materials in the same order, performing the final preparations before welding pipes, using high-purity argon for automated welding, and so on. In Part 2, regarding the definition of the user space, AstraZeneca assigned a senior project manager named Kenneth Borch Larsen. He was responsible for defining the space to be used by users; by using software for computer simulations, he was able to present an accurate representation of the completed space along with its accompanying facilities. What end-users care most about is the appearance of the high-cleanliness areas. He has a very clear and distinct division of areas, including the filling kit area, the ingredient preparation area, the component preparation area, the component processing and modification area, and so on. And coincidentally, these are precisely the areas with a high proportion of process pipelines. Once the installation locations of the equipment in these areas are determined, the engineers focus on how to maximize space utilization. Through computer simulation, visitors (engineers or operators) can experience firsthand what it’s like to open the door and enter this designed area, to observe the various devices placed there. Thus, the size of the passage can be estimated to ensure sufficient space for movement between each device. Furthermore, the workspace must be spacious and clean, with all equipment and items neatly arranged. This solid dosage form production line project includes 20 cleanrooms ranging from Class 100 to Class 10,000. The number, location, and usage points of the sinks must be specified in detail in advance, along with the proper arrangement of high-efficiency air filters, HVAC systems, temperature controllers, and piping. To avoid dead corners or disordered arrangements in pipes and ducts, it is also necessary to specify the corresponding reserved spaces. Computer simulation can not only serve as a guide by providing sufficient details for developing a specific plan for the writing process, but it can also minimize design changes. If the computer drawings of a specific process panel can show the exact location of the valves on the pipes, it can provide the installation manager with very useful guidance. In a simple project, using computer simulations can not only save nearly 10% of the project costs but also help the client obtain what they need. Part 3: Contractor. The contractor is primarily involved in the construction of projects in the biopharmaceutical or solid dosage form industry; he serves as the liaison between the architectural design firm, the end users, and the construction team. Jonas Nilsson is the project manager for this project, and his main task is to oversee the progress of the entire project. The contractor must prepare the main documents for installation, which are referred to by industry professionals as CQP. CQP consists of a set of written SOPs and guidelines for controlling the construction process. The program includes document editing, system and device test files, as well as requirements for the handover package. The program written must ensure that the important systems and components of pharmaceutical equipment are installed according to the specified technical parameters. Additionally, the specific installation parameters must be documented to ensure that current operating procedures (cGMPs) comply with the requirements set forth by the U.S. Food and Drug Administration (FDA). The FDA does not tell people how to manufacture the equipment, but it checks whether all the prepared documents are correct, and it also tells people how to verify the correctness of all those documents. End users and their verification and quality assessment personnel must prove that they meet the requirements of paragraph (a) of 21CFR211.65. This text states as follows: “The equipment used in manufacturing must ensure that there is no reaction, addition, or adsorption between the contact surfaces of its components and the raw materials or drugs being produced, thereby preventing the safety, identity, potency, quality, or purity of the resulting drugs from exceeding the requirements set forth by official or other regulations.” ”If any documents submitted to the FDA certification authority are found to be non-compliant, the FDA certification authority will trace the root cause of the problem until it is resolved. Part 4 On-site Installation Supervisor Project manager Kenneth Borch Larsen said that in a perfect world, he would only need to inform the supplier of the need for process piping installation, and then the piping could be installed according to standards or even in the way he envisioned. But the world isn’t perfect; he must contact suppliers to learn about their price levels and technical expertise. The person in charge of on-site installation for this project used to work for Socar; he is a recognized expert in this field. His responsibilities mainly include design support as well as project coordination and execution. His welders have extensive experience in using automatic welding equipment; they are well aware of the requirements that the system must meet, how to achieve isometric shapes, and how to support pipes in the best possible way. Since the factory was built, appropriate pipe support has become particularly important; it must meet the requirements for areas subject to seismic activity of level 4. Part 5: IQD Handover Package. During the preparatory work for the first phase of pipeline installation, the installation supervisor prepares an IQD handover package for each system, in order to facilitate the connection of industrial wastewater, cleaning steam, etc. Each package includes a scope of work report, a list of project personnel along with their professional certificates, proof of welding work, welder qualification certificates, welding procedure qualifications, and records of process conditions in accordance with ASME Section IX codes for boilers and pressure vessels. It also includes the certification for the welding equipment, the records of material receipt inspection, the axonometric drawings of each pipeline, the certification for the purification materials, and the pressure test reports for various component systems. The welding system includes records of all aspects, welding records, pipeline endoscopy records, as well as the procedures for pickling and passivation along with related certifications. At the end of the IQD handover package process, the client voluntarily signs for receipt of the handover package. The installation supervisor converts the 2D engineering drawings designed by the architect into 3D isometric construction drawings, and then verifies the feasibility of those drawings. Generally, the person in charge must obtain local permits before starting construction. Part 6 Automatic Welding: Over the past decade, the use of automatic welding in biopharmaceutical systems has grown rapidly, and it now almost completely replaces all manual welding. Dr. Charles Campbell pointed out at the recently held ASME BPE standards conference that 99% of pipeline installation welding in biopharmaceutical facilities is carried out using automated welding. This is a requirement of the BPE standard; if manual welding is used, permission from the owner must be obtained, and a pipe endoscope must be used to inspect the interior of the fabricated pipe. The welding equipment commonly used in hygiene-grade biological agent projects is automatic GTA welding equipment. This process mainly takes place in an inert gas atmosphere, where a welding torch generates an arc between the tungsten electrode and the weld seam in order to fix the pipe or fitting in place; the electrode on the torch moves around the joint through a rotor. Welding parameters such as welding current, electrode movement speed, and pulse duration are programmed into the microprocessor-controlled power supply, and welding procedures or processes for pipes or components of different sizes are stored; furthermore, these processes must be printed out and included in the welding qualification documents. The welds are required to have a shape that matches that of the pipe’s cut surface, which should be circular, with no cracks present. The purpose of automatic welding is to achieve a high degree of repeatability from weld to weld; this is not only to ensure high efficiency but also to deliver the best possible quality. On the one hand, the automatic welding machine carries out welding operations using precise welding parameters; on the other hand, it is necessary for the person in charge of installation and his welding staff to be able to control other factors that can affect welding stability. These welders must receive specialized training on this equipment, be proficient in every pipeline welding procedure, and know how to deal with the changes in thermal cycles during welding. The installation supervisor is also responsible for developing Standard Operating Procedures (SOPs) that detail all aspects of the automatic welding process. Part 7 Standard: AZ Company hires a third-party QA company to inspect the quality of automatic welding. In addition to verifying in accordance with ASME IX sections and B31.35, inspectors must also visually check whether the welds meet the standards for ASME biological processing equipment (BPE-2002). The BPE standard was first published in 1997 and revised in 2002; it was the first standard specifically recommended for the use of automated welding in the biopharmaceutical industry. In terms of dimensions and tolerances, to improve compatibility with automatic welding, the BPE standard also provides relevant specifications regarding the applicable ranges for wall thickness, the ellipticity of the welded ends of fittings and other biological facilities, etc. Since the welding current is roughly proportional to the wall thickness – that is, 1 ampere of current corresponds to a wall thickness of 0.001 feet – even a change of one thousandth of a foot can affect the penetration depth of the weld. The verticality of the welds also needs to be well controlled to prevent the formation of significant cracks. Additionally, it is necessary to ensure that the welded components match each other and are arranged neatly. In biopharmaceutical applications with high cleanliness requirements, the commonly used materials are mainly 316 or 316L stainless steel. For welding, 316L stainless steel with a lower carbon content is the best material, as in materials with higher carbon content, carbon atoms tend to migrate to the grain boundaries during welding and combine with nearby chromium atoms to form chromium carbide precipitates, thereby reducing the chromium content at those grain boundaries and leading to intergranular corrosion. However, since the formation of chromium carbide also depends on time and temperature, automatic welding allows for more precise control of heat input compared to manual welding, thereby reducing the formation of chromium carbide precipitates. To ensure welding quality, the DT section of the BPE standard requires that the sulfur content in 316L stainless steel used for welding components and at the weld ends be kept within the range of 0.005–0.017 Weight%. This is the same sulfur content range required for ASTMA270 S-2 pharmaceutical-grade piping material, and it contrasts with the AISI quality specification (0–0.03 wt%). The thermal cycle changes that occur during the metal chemical reactions in stainless steel have a direct impact on the welding quality, and this is also one of the main factors contributing to welding incompatibility. By adopting this standard for sulfur content limitation, some uncertainties in the processing process can be eliminated, thereby **improving the compatibility of automatic welding. When the materials arrive at the construction site, the installation supervisor must check whether the materials meet the requirements as recorded in the form, after which third-party QA personnel will conduct an inspection and make corresponding records. Chapter 6 of ASME B31.3, Pipe Fabrication, clearly distinguishes between the definitions of inspection and testing: \"Testing\" refers to the activities carried out by the owner’s inspectors or their representatives on behalf of the owner, whereas \"inspection\" denotes the quality control actions performed by the manufacturer, producer, or installer – in this case, the person in charge of installation (QC). As for the welding conditions, detailed instructions are provided in the material joining section of the BPE standard. Part 8 Installation: During the installation of the process piping system, automatic welding operators must work closely with quality inspectors. During welding, inspectors must inspect each weld on-site in a timely manner; otherwise, once the entire structure is completed, it will be impossible to examine all the welds using a fiber endoscope. The welds on the product’s contact surfaces must meet the visual criteria for material joints as specified in the ASME BPE-2000 standard. This standard is set primarily to ensure that no microorganisms grow on the weld surface, thereby preventing contamination of the entire system. For example, bacteria often grow in unpenetrated welding cracks, and they cannot be completely removed even with cleaning systems. Dents or misalignment on the inner surface of the weld can hinder the pipe’s drainage, leading to cleaning problems. Therefore, the owner and the person in charge must predetermined in advance, in accordance with AWSD18.1/D18.2.8, the acceptable level of color change during automatic welding. The discoloration and heat-affected zones that occur during welding due to incomplete oxidation removal reduce the system’s corrosion resistance. Any undetected welding defect can lead to contamination of the entire system, which not only violates the requirements of 21CFR 211(a) but also incurs higher costs for correction. When a qualified welder begins working, he first turns on the power to the automatic welding machine, and then determines the dimensions of the pipe or other components to be welded, in order to select the appropriate welding tips as well as the length of the clamps and tungsten electrodes. Then, adjust the welding head by selecting an appropriate power supply speed. In this process, high-purity argon gas is commonly used to fill the weld joint, which not only protects the outside of the pipeline but also purifies its interior. Part 9: Samples Before proceeding with welding, the welder must first create welding samples, and the material of these samples must be the same as that of the components to be installed. Although the sulfur content in 316L stainless steel is strictly controlled within the BPE range, different heating conditions caused by changes in current can still lead to variations in welding penetration. Therefore, a successful sample can prove to the inspector the proper assembly of the machinery and the skilled work of the welders. The first sample made on that day was called a “test sample,” and the welder used it as a reference for the “test sample.” The sample welding must produce a genuine weld joint, rather than merely forming weld beads on the surface of the pipe, in order to determine the validity of the equipment and the process used. After welding, the welder must use a stainless steel brush to remove any external oxidation, burrs, and sharp edges at the ends of the sample, after which the sample is handed over to an inspector for testing. Part 10 Standard Sample Quality Assessment Form: Every welded sample, whether good or bad, must be recorded in the welded sample log. The welded samples are identified using the machinery and equipment employed; in this project, labels A or B are used, on which the sample’s welding number is indicated, such as SWA001, the date, and the welder’s ID. Welding time, date, material heat treatment furnace number, argon certificate, weld joint of the track welder, power supply number, etc., all need to be recorded, and they must also pass inspection by the inspector. All this information must be cross-checked with the relevant documents of the welder’s procedure held by the installation supervisor. Routine sample testing is necessary in the event of changes in power supply, power consumption, adjustments to purification settings, or changes in the welders. Furthermore, when a welded product is rejected, the sample must be thoroughly inspected again; only after it passes the inspection can the next steps in the process be carried out. Part 11 Desktop Welding: Once the sample is approved, the welder gets ready to weld the product. At this point, he needs to decide whether to use bench welding or field welding, whether to connect the inside of the clean pipes to the system or merely perform prefabricated welding of the components. Desktop welding is primarily used within the protection zones of exhaust sleeves with a length of over 20 feet that are prefabricated on-site in advance. This exhaust sleeve can accommodate up to three 180° bendable elbows or two 90° bendable elbows for the installation of endoscopes. The BPF standard requires that the outer surface of the weld be 100% visible visually, and at least 20% of the interior of the weld or the joint edges must be observable. This type of endoscope is highly flexible and is also known as a fiber endoscope. The person in charge of installation is responsible for knowing the length of the pipes to be cut, so that the fabricated exhaust sleeves can be placed exactly at the precise positions indicated on the axonometric drawing. Cut the welded ends to form a square welding joint; clamp the parts using vices and tilt the pipes at an angle of 0.6° as required by ISO standards. These are all manual spot welds performed before welding. During spot welding, it is necessary to fill the area with clean, high-purity argon gas to prevent oxidation, which could result in the welds formed through automatic welding not melting completely. Incomplete spot welding is the main factor causing defective welds. All welds on the exhaust pipe must pass inspection by an inspector using an endoscope before assembly can proceed. Water-cooled weld joints can be used on-site to enable high-load welding and improve production efficiency. Before inspection, the weld scale on the welds must be removed with a scouring pad. According to the SOP, high-purity argon is still pumped into the inside of the clean pipeline until it has completely cooled down. Part 12 Field Welding: Most field weldings or spot weldings involve welding exhaust sleeves or connecting exhaust pipes to long pipelines. The purity of argon is crucial for all welding processes, especially field welding, as welding must take place under the protection of high-purity argon to prevent oxidation. The internal pressure of argon must be sufficient to deliver the gas to the weld area without causing overpressure; otherwise, overpressure at the liquid melt pool can lead to internal depressions or even damage to the weld seam. On-site, the gas flow rate is adjusted by changing the pipe diameter and the distance from the pipe outlet, so that welding under any constraints takes place within an appropriate pressure range. If there are branches in the system, such as welds on steam pipes, it is also necessary to change the airflow; in that case, the gas flow rate will become twice that of when there are no branch welds. When one of the branches loses its cover, a flow regulator must be installed at the outlet of the other branch in order to keep the internal air pressure within a reasonable range. The oxygen gauge is used to monitor the internal argon pressure in order to ensure welding stability. Planned inspections are necessary for on-site welding; for the on-site welding of some intermediate pipes, endoscopes must be used to conduct inspections from the ground, and the slope of each pipe turn also needs to be checked. For this work, the required slope is 0.6° or 1%, which is a slope of about 1/8 inch per foot. The number of slopes can vary depending on the workload and pipe length, but it is necessary to ensure the proper operation of the entire drainage system. The welding number is designated by quality control, recorded in the welding record sheet, indicated on the axonometric drawing, and also engraved on the pipe. The information contained in the welding log and pipeline-related documents is of the same type as that recorded in the sample log. All welding tasks, whether performed in a laboratory or on-site, must be recorded in the welding log, regardless of whether they have been inspected or not; only the welds that have been inspected are recorded in the internal inspection log. Welding quality cannot be incorporated into a testing system; it is similar to welding equipment, welding procedures (SOPs), materials and surface finishing, gas quality, cutting, cleaning, assembly, and the operator’s qualifications. Third-party quality management ensures that welding equipment operates properly, and that the installation personnel follow their own standard operating procedures (SOPs). Quality standards such as BPE-2002 help owners, installation contractors, and inspection officers understand the expected quality level of the completed system. The use of automated welding greatly improves the quality of repeated welds, resulting in a pipeline system with higher cleanliness. All of these are essential for producing high-quality biopharmaceutical products. Part 13 Automatic Welding: Automatic welding is widely used in the manufacture of equipment slides, such as CIP slides or those for WFI production distillation furnaces. The various components on the slides are connected using a considerable number of stainless steel pipes; these slides are assembled by the supplier through automatic welding and then sent to the pharmaceutical factory for installation. When installing the slides on-site, all such welding and on-site welding must meet the same quality management requirements. The welding during the slide production process also needs to be inspected by the supplier. Part 14 CAD Axonometric Views: At the end of the work, all axonometric views need to be entered into the computer. Automatic welding is widely used in the manufacturing of equipment slides. By using “plantNorth”, all the separate axonometric drawings are compiled into a single document, which is then stored on a CD for permanent preservation. Part 15 Pressure Testing: After the pipeline system is installed, a pressure test must be conducted before the passivation process. This pressure test is primarily supervised by the testing supervisor; it involves filling the pipeline system with clean nitrogen or argon to raise the internal pressure to 1.5 times the design pressure, or even higher, and then monitoring the pressure drop over a period of four hours. If there is no pressure drop, the system is considered qualified. Of course, this can only be done using certified measuring instruments equipped with scales. Another safer method is to use soft water as the testing medium, filling the pipes with it, and using an exhaust valve, a water inlet valve, and a calibrated pressure gauge. This method is relatively safe; it does not cause people to faint. In the worst case, there may be a leak. Part 16 Pickling and Passivation: The heat treatment in the stainless steel production process causes a chromium oxide film to form on the metal surface, reducing the chromium content in iron. During the welding process, the passivation layer breaks down, causing the elements at the weld and heat-affected zone to redistribute; no passivation film is formed any longer. As a result, the iron content on the surface of the weld increases, while the chromium content decreases sharply. Before the system is put into operation, if no chemical passivation is carried out, the system, especially the weld points, will develop rust due to reduced corrosion resistance. The purpose of acid washing and passivation is to remove free iron and other anodic contaminants from the surface of stainless steel, in order to obtain the same passivation film. During welding, it is necessary to avoid or remove the tempered chromium oxides and iron oxides that form on the surface of stainless steel. Even with mild tempering, passivation cannot completely remove it, because the depth of effect of passivation is only 50 Å, whereas the depth of tempering can reach 400 Å or even more. Although passivation raises the tempering pitting potential of the weld, indicating that it can restore the corrosion resistance reduced during welding, corrosion that occurs at the tempering passivation layer generally takes place first in the heat-affected zone. The tempered oxides in the welds and heat-affected zones can be removed by mechanical grinding, solutions of nitric acid and hydrofluoric acid, or acid pickling with adhesives. This treatment can also be used to remove metal from the area beneath the tempering layer, but it may lead to a decrease in chromium content. While it helps restore corrosion resistance, it also makes the surface of the stainless steel rough; therefore, the treated surface needs to be polished and passivated. Portable electrolytic oiling devices can remove tempering oxides while preventing surface roughness, but they also remove metal, thereby altering dimensional tolerances. During pipeline installation, the most effective and practical way to maintain the corrosion resistance of the pipeline system is to use high-purity argon gas during automatic welding; this prevents the formation of visible tempering discolorations and avoids contamination of the system by carbon steel tools or any other type of iron-based contaminants. The process is completed with a chemical passivation treatment. Passivation pretreatment is a key step in getting the system online, and it is essential for preventing corrosion in stainless steel systems under high-temperature operation or in aggressive chloride environments, as well as when ultra-pure water is used. At the AZ factory, a sodium hydroxide cleaning solution is commonly used to remove construction residues, organic films, surface coatings, as well as aluminum, sulfides, and other contaminants. During the automatic welding and installation of the system, a passivation agent composed of citric acid, a reducing agent, and EDTA is commonly used for passivation. In addition to removing free iron, just like nitric acid or other inorganic acids, it can also dissolve surface contaminants as well as most of the impurities that can cause pitting. The function of the passivator is to prevent iron from adsorbing on the surface, thereby making it easier for free iron to be washed away from the system. The use of citric acid as a passivating agent not only enables the surface to achieve an optimal Cr/Fe ratio, but it is also safer and less polluting compared to other inorganic acids such as nitric acid. However, pickling and passivation still cannot overcome the damage caused by improper gas injection during automatic welding. Part 17: Verify that Company AZ has its own verification team, which possesses an overall plan for verification. Each system, such as WFI, CIP, steam cleaning, etc., has its own separate validation draft. This verification team conducts random inspections during system installation; they hire third-party quality assurance (QA) firms to work directly for AZ Company. The owner is responsible for cooperating with the FDA to ensure that all work is carried out in accordance with current good manufacturing practice (cGMP) regulations, and that there is corresponding documentation to prove this. Part 18 Risk Changes When a device is ready, users can use it. Once this system is put into operation, the operator can find better ways to carry out his work, which may include moving the pipes – another typical type of change. Over the next 4 to 5 years, this vision of change will gradually become a reality, and as a result, the demand for equipment may also change. The FDA has approved the drug and established a licensing relationship with AZ Company, but there remains a risk that it may not be approved; therefore, the equipment needs to be modified in order to produce different drugs. They may need to switch to a different system in order to produce new drugs, or when there is a high demand for the drugs being produced, they might also need to improve the performance of the system in order to increase production volume. This may require adjusting the flow rate of the water supply system or changing the operating temperature. Unexpected changes can create tensions in public utilities, water supply, and infrastructure. KennethBorch Larsen often enhances his system to enable it to change according to different requirements.