How to Maintain Water for Pharmaceutical Use in Production Lines

In the manufacturing of pharmaceuticals, Water for Pharmacutical Use, (PW, WFI, etc.), goes beyond the conventional understanding of a simple raw material; rather, it represents a key component intricately tied to global Good Manufacturing Practices (GMP) regarding the safety, effectiveness, and regulatory approvals of a drug. The lack of adequate upkeep to the pharmaceutical water system could be a breeding ground for microbial contamination, chemical residue, and, in the worse scenario, industrial production halts and dangerous ramifications for consumers. Thus, it is crucial that pharmaceutical companies construct a strategic and careful plan of action for the upkeep of pharmaceutical water within production lines. The aim of this article is to outline and present the foremost steps as well as the optimum strategies to guarantee the continuous and reliable quality of water performed and utilized in the production.

Development of an Automated Water Quality Monitoring System.

The first and most vital step in keeping pharmaceutical water pristine is to establish clear and continuous record keeping of the water quality metrics. Implementing salient collection strategies as well as a robust pharmaceutical monitoring system ensures that the needed standards are met and avoids any cross contamination scenarios.

First, establish key monitoring parameters related to the specific type of pharmaceutical water. The system for Purified Water (PW) includes monitoring of pH, conductivity, TOC, TOC, and microbes, whereas Water for Injection (WFI) has additional endotoxin testing and more stringent parameters. Monitoring parameters must comply with (USP, EP, CP standards) and global regulatory standards.  

Second, use a combination of online and offline monitoring. Online sensors may measure conductivity and temperature, and send alerts when certain values are too high or too low. Offline monitoring may involve testing for microbes, TOC, and other parameters during specific intervals like daily for microbes and weekly for TOC, and provides deeper assessments than online sensors may detect.  

Third, take all the steps necessary to store all monitoring data in an organized fashion. All records should be retained and maintained properly including the corrective action records, the time and date, the operator and every other relevant detail. The records should be in compliance with water quality regulations for audits.  

Implement Regular Cleaning and Sanitization Protocols  

Pharmaceutical water system contamination may arise from biofilm, mineral scaling, or chemical residues. In order to reach system’s optimum state of performance, regular sanitization and cleaning protocols are vital to diminish these risks.

First, create a cleaning schedule based on the system design and usage frequency. For instance, storage tanks and distribution loops might need sanitizing on a weekly basis, while the RO membranes in the water purification system need cleaning to remove fouling on a monthly basis. Scheduling in accordance with production cycles is critical. All cleaning and sanitizing while production is in cycles is almost completed cleaning and the disruption is minimal, also thus cleaning is workable.
 
Second, choose a cleaning and sanitizing agents that are pertinent to the task at hand. These materials need to be in synergy with the system components and materials like stainless steel and plastic in order to avoid problems of corrosion and leaching. A safe listing of agents consist of hot water (sanitizing agent), citric acid (descaling agent), and hydrogen peroxide (microbiocide). At all times, such agents need to be pharmaceutical grade with excess leaching and residue to protect the water from contaminating agents.
 
Thirdly, if applicable, follow accepted protocols for cleaning. Each cleaning, elimination of foreign junctions of the system, and anything that goes together, should be done in a way that verification is used to prove that the system is clean. After cleaning the system, this step is vital to make sure that the desired components are kept to avoid human errors.

Systematically Maintain the Water Purification Equipment. 

The essential components of the pharmaceutical water systems such as the RO membranes, ion exchange resins, filters, and pumps, all of which require a high degree of  professionalism. These components should be maintained routinely in order to avoid unanticipated malfunctions and guarantee that the water purification is as effective as it should be.

First, perform scheduled inspections, maintenance, and replacement of consumable components. For instance, future pre-filters should be replacement every one to three months depending on the presed amount of sediment in order to prevent clogging. However, ion exchanger resins on the other hand, have a lifespan of 1 to 2 years and should be replaced once their capacity to remove impurities declines. In the case of Reverse Osmosis (RO) membranes, these can last 2 to 3 years, however, these also need to undergo routine testing for leaks and need to be properly maintained.  

Second, keep tracks on the performance of critical equipment. Specialized parameters to be them monitored in the case of an RO system include pressure, flow rate and rejection rate. If there is a sudden and unexplained increase in pressure, or drop in rejection rate, this might signal membrane damage or fouling and should be checked immediately. Other important components like pumps and valves should also be checked regularly for leaks, and abnormal noise. If neglected for a long time, these could cause system contamination.  

Third, keep systematic and organized maintenance records. Report on every maintenance part of the system which include, but not limited to component replacement, and performance testing is critical records for every device. These records are essential to keep track the system components lifespan, maintenance and audit optimization in compliance with Good Manufacturing Practice (GMP) system.  

Proper Control Over Water Storage and Distribution System  

Contamination is not exclusive to the untreated waters. Even purified water can become contaminated if storage and distribution is not managed well. Stagnant water and inadequate loop circulation are major factors risking water quality.

First, the operation and design of the storage tank needs to be optimized. Storage tanks should be constructed of 316L grade stainless steel (known for its non-corrosive and antimicrobial properties), and the tanks should be constructed with a conical bottom for effective drainage. A slight positive tank pressure (using filtered air) will be required to keep atmospheric contaminants from entering the tank. Also, overfilling the tank must be avoided. Even circulation reduction can lead to stagnation.

Second, circulation should be maintained in the distribution loops. Stagnant water in ‘dead legs’ (used, unused, or straight portions of a loop) is an easily accessible and optimal location for microbes to breed. Design distribution systems so that ‘dead legs’ do not exceed a total length of 6 times the pipe diameter, and then, ensure that water circulates and maintains a velocity of 1–3 m/s, so that sedimentation and microbial adhesion do not occur.

Third, regular storage and distribution system sanitization is required. In addition to routine sanitization, periodic "shock sanitization" is required to eradicate any persistent biofilms that may remain within the system. Following this procedure, the system must be flushed completely and must be tested to ensure that no sanitizer remains within the system.

Train Employees on Operational Procedures and Routine Maintenance of Systems  

Deviations in water quality are often caused as a result of human error. Make certain that personnel operating and maintaining the pharmaceutical water systems are fully trained and qualified to execute the procedures.  

First, create a training strategy that focuses on the individual's responsibilities. Daily system monitoring and recording, system startup and shutdown, and basic troubleshooting all require training. Maintenance technicians are expected to be trained on the more advanced topics of equipment repair, component replacement, and system validation. Quality control personnel are expected to be trained on the water testing procedures and regulatory framework.  

Second, training does not stop at the initial training. As regulatory norms and acceptable best practices change, the staff must also be brought up to date. Complacency sets in and the key procedures become forgotten, which is what such recurrent training is designed to counter.  

Third, the training must be reviewed and the level of competence must be identified. All training sessions must be recorded, along with the names of the attendees, and the date and the topics discussed. Regular assessments such as written exams or practical assessments must be used to ensure that the staff are able to apply their learned material. Competency assessments are necessary to fill in the knowledge gaps with more precise training.

Prepare for and Respond to Water Quality Deviations

Water quality deviations can sometimes occur despite our diligent efforts to maintain standards. Having a defined process in place for managing deviations can minimize issues to address and impacts to production and compliance.

First, set up a protocol for deviation response that is simple and clear. Part of a system (i.e. tanks, filters and tubing) needs to be isolated as soon as a deviation occurs (e.g. in microbial counts) to avoid further contamination. Rapid notification is required of quality control, maintenance, and production so that they can set up a plan of action.

Second, what caused this deviation? For a defined problem, what caused this deviation? Utilizing various tools (fishbone diagram, 5-Why, etc.), identify whether the cause was a broken piece of equipment, insufficient sanitization, or some form of human error. No matter what the issue, we do not want to see the same problem in the future.

Third, define and implement the corrective and preventive actions (CAPAs). In this case, leakage of a defective replacement filter requires corrective action, and the balance of failure avoidance requires stringent control procedures as defined in the preventive actions. The process of deviation management is of the utmost importance and therefore should be documented for future reference.