In the pharmaceutical industry, water is one of the most critical services. It is used as a raw material, solvent, cleaning agent and essential component in numerous formulations. Its quality directly impacts patient safety and regulatory compliance of products. Therefore, water generation, storage and distribution systems must be designed, qualified and maintained under strict standards of the Good Manufacturing Practices (GMP).
The water system qualification It constitutes a fundamental stage within the life cycle of the system. Its objective is to demonstrate, through documented evidence, that the system is capable of producing water with the physicochemical and microbiological characteristics established for its intended use, whether purified water (PW), water for injection (WFI) O ultrapure water, and that can maintain these parameters constantly over time.
How to select the appropriate type of water according to your pharmaceutical use
The European Pharmacopoeia (Ph. Eur.), USP and other international standards define the different grades of water used in pharmaceutical manufacturing, each with its own specifications.
- Purified water (PW): used in the preparation of non-sterile medications, cleaning of equipment and intermediate formulations. It is obtained through processes such as reverse osmosis, ion exchange or electrodeionization.
- Water for injection (WFI): used in the production of parenteral medications and sterile solutions. Traditionally it was generated by distillation, although the latest guidelines allow the use of double pass reverse osmosis combined with other validated technologies.
- Ultrapure or laboratory water: intended for analytical testing and high sensitivity applications.
Compliance with the limits established for conductivity, total organic carbon (TOC) and microbiological count It is mandatory and must be demonstrated throughout the entire distribution network.
Stages of the water system qualification cycle
The qualification of a water system follows the stages defined in the GMP validation life cycle:
- DQ (Design Qualification). The proposed design is reviewed and documented to meet user requirements (URS), engineering standards and applicable GMP regulations. Includes construction materials, sizing, flow paths, slopes, sanitary valves, and sanitation strategy.
- IQ (Installation Qualification). Verifies that the installation has been carried out in accordance with the approved specifications. Components, orbital welds, sanitary connections, instrumentation and calibration records are inspected.
- OQ (Operational Qualification). It demonstrates that all subsystems (generation, storage, distribution and control) operate within established operating ranges. Includes tests of alarms, flows, temperatures, pressures and thermal or chemical sanitation controls.
- PQ (Performance Qualification). Evaluates the system's ability to produce and maintain water according to specifications under real operating conditions. It is generally carried out over a period of 2 to 4 weeks, with sampling at critical points and microbiological and physicochemical analyses. It is recommended to carry out PQ1 before the installation enters into service, PQ2 after 4 weeks of service (with sampling for 10 days) and PQ3 until the end of the year with weekly sampling.
The set of these phases provides the necessary evidence to confirm that the system is adequate, safe and reproducible.
Components and controls that define water system reliability
The robustness of a water system depends on both the design and subsequent control. Some critical aspects include:
Material selection and hygienic design
The construction material must be compatible with high purity water and resistant to corrosion. He stainless steel 316L, with surface finish Ra ≤ 0.6 µm and chemically passivated, is the standard for pipes and tanks. In plastic components, PVDF, PP or PFA are used, previously qualified to avoid leachate or migration.
The hygienic design must avoid dead zones or stagnation that favor microbial proliferation. This involves ensuring adequate slopes (at least 1:100 on return lines), low-point drain valves, sanitary Tri-Clamp connections, documented orbital welding, and full traceability of critical components.
Continuous flow and return configuration
Purified water and water for injections must keep in constant recirculation at flow velocities greater than 1 m/s. This flow ensures a turbulent regime that prevents the formation of biofilms and keeps internal surfaces clean.
The return system must also be designed without dead zones or unnecessary branches. The pressure and temperature must be continuously controlled to avoid condensation that could favor microbial growth.
Periodic sanitation
Sanitation is a basic element to preserve the microbiological integrity of the system. Could be thermal, chemical or one combination of both:
- Thermal sanitation (70–85°C): Highly effective, especially in hot loop water for injection (WFI) systems. Requires automated control and validation of thermal uniformity.
- Chemical sanitation: It is used in purified water systems where it is not feasible to maintain a high temperature. The most common agents are ozone, hydrogen peroxide or peracetic acid, and their validation includes efficacy and rinsing tests.
Each method must have validated protocols that demonstrate the expected microbial reduction and the absence of chemical residues after the process.
Online monitoring and control of critical parameters
A modern pharmaceutical water system must include validated and calibrated instrumentation that allows continuous monitoring of critical parameters:
- Conductivity: instant indicator of ionic purity.
- TOC (Total Organic Carbon): evaluates the presence of dissolved organic matter.
- Temperature and pressure: allow you to control the loop environment and prevent condensation.
- Flow rate and flow rate: they guarantee the turbulent regime and correct recirculation.
Automated systems should include alarms configured with action and warning limits, as well as traceable electronic records that comply with 21 CFR Part 11 or Annex 11 of European GMP.
Design of use and sampling points
The points of use are the places of greatest microbiological vulnerability in the system, so their design is decisive. They must be equipped with sanitary total drain valves, no dead zones, and kept closed when not in use.
Sampling points must represent the entire distribution network: generation, tank, return and critical outlets. The sampling plan validation It must consider the frequency, sample volume and analytical methods used.
Microbiological control and biofilms
The biggest challenge in operating a water system is the formation of biofilms. These microbial structures can resist disinfections and release contaminants intermittently. Prevention is achieved through:
- Design without stagnation areas.
- Constant temperature and flow.
- Regular and validated sanitations.
- Frequent microbiological monitoring, with analysis of trends and alert limits.
Integration with the control and maintenance system
The water system must be integrated into the Validation Master Plan (VMP) and preventive maintenance program. Any intervention (replacement of components, calibrations or structural modifications) must managed through change control, evaluating its impact on the validated state of the system.
Critical control parameters: supervision and corrective action
To ensure the continuous performance of the water system and maintain GMP compliance, it is essential to establish a documented monitoring plan that defines the critical variables, their acceptance limits, the control frequency and the actions to be implemented in the event of deviations.
Below is a summary table with the main critical parameters of pharmaceutical water systems:
| Parameter | Control objectives | Acceptance Range/Limit | Monitoring frequency | Corrective Action for Deviation |
| Conductivity | Ionic purity control | ≤ 1.3 µS/cm (at 25 °C) for PW / ≤ 1.1 µS/cm for WFI (according to Ph. Eur.) | Continuous (online) | Check sensor calibration; check ion exchange or reverse osmosis resins; investigate sources of ionic contamination. |
| Total Organic Carbon (TOC) | Detection of organic contaminants | ≤ 500 ppb (0,5 mg/L) | Continuous (online) / Daily | Validate instrument; inspect prefilters and UV lamp; perform chemical sanitation if necessary. |
| Temperature | Prevention of microbial growth | ≥ 65 °C in hot return systems / 15–25 °C in controlled cold | Continuous (online) | Check thermal controllers and valves; check insulation; activate thermal sanitization. |
| Pressure | Ensure stable flow and avoid return contamination | Depending on design (usually 2–4 bar) | Continuous / Daily | Check recirculation pumps and valves; Inspect for possible leaks or blockages. |
| Flow rate / Flow rate | Maintain turbulent regime (avoid biofilm) | > 1 m/s | Continuous / Weekly | Clear lines; check pumps; confirm correct valve balance. |
| Microbial Count | Assess microbiological contamination | ≤ 100 CFU/mL for PW / ≤ 10 CFU/100 mL for WFI (Ph. Eur.) | Weekly / According to risk | Perform sanitation; review points of use; analyze microbial growth trend. |
| Bacterial endotoxins | Check absence of pyrogens | ≤ 0.25 EU/mL (for WFI) | Monthly / According to risk | Immediate sanitation; review of the generation system; analytical reinspection. |
Note: The limits may vary according to the specifications of the current pharmacopoeia (Ph. Eur., USP, JP) and must be adjusted to the classification of water used and the intended use.
Revalidation and continuous monitoring
The qualification of a pharmaceutical water system does not conclude with the completion of the PQ (Performance Qualification). According to GMP, validation is a living and continuous process throughout the system life cycle. This involves implementing a systematic program of periodic revalidation and real-time monitoring, intended to confirm that the system maintains its controlled and validated state under normal operating conditions and over time.
Revalidation as part of the life cycle
Revalidation consists of repeating, with a defined frequency or in the event of significant changes, critical tests that demonstrate that the system continues to meet its specifications.
It should be included within the Validation Master Plan (VMP) and aligned with the quality risk management (QRM) approach, in accordance with the ICH Q9 guideline.
Los typical cases that require revalidation include:
- Structural modifications to the system (for example, replacement of tanks, pumps or osmosis membranes).
- Changes in critical operating parameters or in the sanitation strategy.
- Repeated deviations or results out of specification.
- Major maintenance interventions or prolonged periods of inactivity.
- Established periodic review (normally every 1 or 2 years, depending on criticality).
The scope of revalidation must be defined through an impact assessment documented, avoiding repeating all the original tests if not necessary. This approach optimizes resources and aligns with modern trends in Computerized Systems Assurance (CSA) and continuous risk-based validation.
Continuous monitoring: guarantee of controlled status
Continuous monitoring is the basis of maintaining validated status. Through instrumentation and data acquisition systems (validated SCADA, PLC or BMS), the critical system parameters are recorded and analyzed in real time: conductivity, TOC, temperature, flow and pressure. These values must be compared to defined alert and action limits, which allow action before a real deviation occurs.
The integration of these systems with trend analysis platforms makes it possible to:
- Detect incipient deviations or abnormal patterns (e.g., gradual increase in OCD or repetitive microcontamination).
- Evaluate the effectiveness of thermal or chemical sanitation.
- Generate automatic alarms and auditable reports in accordance with 21 CFR Part 11 / EU GMP Annex 11.
- Optimize preventive maintenance through predictive analysis, avoiding unplanned interventions.
Monitoring must be complemented with a program of microbiological and physicochemical sampling, in which the results obtained by online systems are verified with laboratory tests. This correlation between electronic data and analytical results guarantees the reliability of the instrumentation.
Trend review and performance analysis
A key part of continuous monitoring is periodic review of trends. Based on the historical data collected, the system behaviors to identify subtle variations that could anticipate larger deviations.
These reviews must be formally documented and part of the Product Quality Reviews (PQR) or of the Annual Quality Reviews (AQR) required by regulatory agencies.
Trend analysis also allows:
- Optimize the frequency of sanitation.
- Adjust alert limits based on actual performance.
- Detect progressive failures in membranes or filters.
- Evaluate the effectiveness of the maintenance program.
Data management and information integrity
All monitoring and revalidation records must be stored in validated systems that ensure data integrity in accordance with ALCOA+ principles (Attributable, Readable, Contemporaneous, Original, Accurate, Complete, Consistent, Durable and Available).
Traceability must allow any event to be reconstructed, including alarms, adjustments or interventions, ensuring immediate availability for audits or regulatory inspections.
The current trend in the industry is move towards intelligent monitoring systems, with support of artificial intelligence and predictive analysis, capable of correlating environmental variables, microbial trends and operational performance to anticipate deviations before they occur.
Validated status review
Periodically, the company must carry out a comprehensive review of validated status of the system, in which it is evaluated:
- The conformity of the design with current specifications.
- The accumulated results of monitoring and sampling.
- The history of deviations and corrective actions.
- The changes implemented and their documentation.
The result of this review determines whether the system remains suitable or requires partial or complete re-qualification.
Qualified water as the axis of the pharmaceutical quality system
The qualification of water systems in the pharmaceutical industry is not only a regulatory requirement, but a tangible guarantee of control, security and confidence. Each stage, from design to revalidation, constitutes a link in the chain that ensures the purity of the water and, by extension, the quality of the final product.
A correctly designed, qualified and maintained system under a life cycle approach allows maintaining traceability, preventing deviations and demonstrating compliance with any regulatory audit. Furthermore, reflects the maturity of the organization's quality system and its commitment to operational excellence.
In an environment where technological innovation and digitalization are advancing rapidly, qualified water systems must not only be compliant, but also efficient, sustainable and adaptable. Integrating online monitoring, trend analysis and predictive maintenance strategies will make the difference between a reactive system and a truly controlled one.
In short, the qualification of water systems is not limited to certifying installations: it represents a quality and responsibility statement, where each drop produced meets the highest standard of purity required by GMP and the industry's commitment to patient safety.