Water is one of the most relevant critical services in the pharmaceutical industry. His transversal use (from formulation to equipment cleaning) and its direct impact in product quality make it a fundamental element within the GMP compliance system.
In recent years, water generation and distribution systems have undergone significant evolution. There has been a shift from solutions based almost exclusively on thermal processes to configurations supported by membrane technologies, more efficient from an energy point of view and aligned with new regulatory requirements.
This technical guide provides an overview of classic technologies, current trends and the impact of the latest regulatory updates, especially the European Pharmacopoeia 12.3.
1. Classic treatments: the consolidated standard
Traditional systems are based on the sequential elimination of contaminants (ions, organic matter and microorganisms).
| Pretreatment | Includes filtration multimedia (sand/anthracite), descaling (ion exchange to eliminate hardness) and activated carbon filtration to eliminate free chlorine that would damage subsequent membranes. |
| Reverse Osmosis (RO) | It is the heart of the classical system. It uses pressure to force water through a semipermeable membrane, retaining 95-99% of salts and microorganisms. |
| Electrodeionization (CEDI) | A continuous process that combines ion exchange resins and ion selective membranes, using electricity to regenerate without the need for chemicals. |
| Distillation (for WFI) | The classic “golden” method. The water evaporates and condenses, ensuring the total elimination of endotoxins and pyrogens. Distillers are used multiple effect or of vapor compression. |
2. Novel treatments and trends (2025-2026)
The great recent revolution is the regulatory acceptance (especially in the European Pharmacopoeia) of methods non-thermal to get WFI.
2.1. Membrane WFI (cold WFI)
One of the most relevant advances has been the regulatory acceptance of the WFI generated by membrane technologies. Since 2017, the European Pharmacopoeia allows the production of WFI using non-thermal systems, provided that adequate control of the microbiological risk is guaranteed.
These systems are usually based on configurations of double pass reverse osmosis, followed by CEDI and a final stage of ultrafiltration (UF). The latter acts as a physical barrier against endotoxins and bacterial fragments, using membranes with a pore size of the order of 0.01 µm.
The main advantage of these systems is the reduction of energy consumption, by eliminating the need to generate steam. However, this approach requires a more robust control strategy, especially in system distribution and sanitation.
2.2. New disinfection and control technologies
The current trend also includes new technologies aimed at improving microbiological control and reducing dependence on chemical products:
- The use of electrolytic ozone allows the generation of ozone on-site directly from loop water for continuous sanitation. Unlike chemicals, ozone is easily removed with UV light before points of use.
- Likewise, they are introducing new generation selective resins, designed to eliminate activated carbon using specific resins to eliminate TOC (Total Organic Carbon) and emerging contaminants such as PFAS, reducing the risk of bacterial proliferation in carbon filters.
- On the other hand, modern RO and CEDI systems are being designed to support thermal sanitization at 80-85°C, which makes it possible to dispense with aggressive chemical agents and improve the robustness of microbiological control.
3. Production of PW, HPW and WFI: technological comparison
| Water type | Main use | Classic method | Novel method |
| PW (Purified) | Non-sterile forms, cleaning. | THINK + CEDI | RO + Membrane Degassing + CEDI |
| HPW (Highly Purified) | Products that require low microbial load. | RO + CEDI + UF | Integrated into dual stage RO systems |
| WFI (Injectables) | Parenteral, ophthalmic. | Distillation | RO Double stage + UF (cold WFI) |
4. Key differences in distribution (Loops)
The quality of water does not depend only on its generation, but also on its distribution. Loop systems should be designed to avoid stagnation, biofilm and microbiological contamination:
- Los PW ties They usually operate at room temperature, relying on periodic sanitization using chemicals or ozone.
- On the other hand, the systems ofWFI azos They are traditionally kept “hot” (self-disinfecting heat at >75°C). Modern “cold” systems require much tighter control of ozone and flow rates to prevent biofilms.
5. European Pharmacopoeia (Ph. Eur.) 12.3: a structural change
The update of the European Pharmacopoeia (Ph. Eur.) 12.3 It is a milestone for the industry, as it consolidates the global harmonization and digitalization of quality control processes.
Published in January 2026, this edition will be mandatory from July 1, 2026. The most critical changes directly affect pharmaceutical water monitoring and data management.
| Changes in Water Monographs (0169 and 0008) | The main goal has been harmonization with the USP (US Pharmacopeia) and simplification of analytical assays. |
| Replacement of the “Oxidizable Substances” test | The test for oxidizable substances (based on color change with potassium permanganate) is definitively eliminated for the Sterilized WFI. However, in the new norm is replaced by the test of Total Organic Carbon (TOC), which is much more sensitive, non-selective and quantifiable. This aligns the requirements of bulk water with those of bottled water. |
| TOC and Conductivity Limit Adjustments | Accuracy in OCD: The limit is redefined from 0.5 mg/L to 0.50 mg/L. Although it seems like a minor change, it requires greater metrological precision in online equipment reports and calibrations.
Conductivity Clarification: The system calibration section has been adjusted. Now, the permitted deviation refers to the expected value of the reference solution and not the measured value, eliminating ambiguities in maintenance audits. |
| New General Chapter 5.38: Data Quality | This is perhaps the most disruptive novelty of edition 12.3, reflecting the digital transformation of the industry.
Approach: Establishes guidelines on the data integrity and quality generated by analytical systems, especially those of digital origin. Key Concepts: Formally introduce the process ETL (Extract, Transform, Load) as a framework for managing data throughout its lifecycle and emphasizes the role of Subject Matter Experts (SMEs) in automated decision making. |
| Review of Chapter 2.2.44 (TOC)
|
To facilitate the implementation of the changes in the water monographs, the methodology chapter has been updated:
New Reference Standards: The traditional chemical reagents (Sucrose R and 1,4-benzoquinone R) are replaced by Chemical Reference Substances (CRS) EDQM officials. Simplification: This reduces variability in the preparation of calibration solutions and verification of oxidation efficiency. |
6. Implement the European Pharmacopoeia
Mandatory from July 1, 2026, the new Ph.Eur.12.3 is not only a change of “roles”, but an operational adjustment in the laboratory and in plant engineering management.
Here's what this means “in the real world” for a pharmaceutical plant:
6.1. Final goodbye to permanganate (Laboratory)
For him Sterilized WFI (packaged), the visual test for “Oxidizable Substances” will no longer be carried out.
From an operational point of view, this implies the withdrawal of this method from the Standard Operating Procedures. In parallel, the measurement of Total Organic Carbon (TOC) also becomes mandatory in this type of samples.
In those cases in which analytical capacity was not available to measure TOC in packaged products (due to equipment limitations or possible interference from the packaging), specific methods will need to be developed and validated. This validation must consider different materials (glass, plastic, bags), ensuring that the leachables from the container do not alter the result above the established limit of 0.50 mg/L.
6.2. Greater precision in measurement
This decimal change seems trivial, but it has legal and metrological implications:
- Rounding Criterion: If the online TOC team marked 0.54 mg/L, previously you could argue that “rounding to a decimal” the limit of 0.5 was met. With 12.3, now is out of specification (OOS).
- Calibration: Service providers should be required to ensure that the calibration certificates for TOC and conductivity sensors reflect this new precision and that the standards used have traceability in accordance with the new standards. CRS (Chemical Reference Substances) from EDQM.
6.3. Implementation of Chapter 5.38 (Data Quality)
This is the most profound change at the level of Quality Assurance (QA):
- Sensor Audit: Water systems (SCADA/PLC) generate digital data. Now it must be demonstrated that the data coming out of the conductivity sensor reaches the final record without alterations (ETL process: Extract, Transform, Load).
- SMEs in the Loop: The standard calls for subject matter experts (SMEs) to review automated decision algorithms. If the system automatically diverts water to the drain when conductivity rises, the logic of that decision and its validation must be documented.
6.4. Use of new reference standards (CRS)
The revision of chapter 2.2.44 introduces a change in the reference materials used in TOC tests.
It is no longer sufficient to use analytical grade reagents, such as sucrose or benzoquinone. Instead, they should be used Chemical Reference Substances (CRS) EDQM officials for System Suitability Test.
From a practical point of view, this change simplifies audit management, since it eliminates the need to justify the quality or purity of internal reagents, directly aligning the assays with the official Pharmacopoeia standards.
6.5. Summary of tasks for July 2026
| Area | Practical Task |
| Quality control | Replace chemical reagents with CRS standards. |
| Quality Guarantee | Update WFI and PW specifications in the management system (ERP/LIMS). |
| Engineering/IT | Check data integrity (ALCOA+) in the water loop records (Chap. 5.38). |
| Records (RA) | Notify changes to the dossier if you have a CEP (period of 3 months). |
6.6. How does this affect your current teams?
If your TOC measurement equipment is more than 10 years old, your software may not allow data export with the level of integrity required by the new chapter 5.38 or may not stably achieve two-decimal precision.
7. Trends in the European Pharmacopoeia
Current trends for 2026 show a unprecedented regulatory convergence between the European Pharmacopoeia (Ph. Eur.) and the FDA (aligned with the USP). The goal is clear: eliminate subjective chemical methods and replace them with real-time, data-driven analytical technologies.
7.1. Global Harmonization (The End of “Oxidizable Substances”)
One of the most relevant trends is the unification of criteria between Europe and the United States in the evaluation of the quality of pharmaceutical water.
Until now, There were differences in the determination of the organic load. However, Ph. Eur. 12.3 marks a turning point by eliminating the permanganate-based “oxidizable substances” test for sterilized WFI, adopting an approach aligned with the USP.
As a consequence, Total Organic Carbon (TOC) is consolidated as the reference analytical standard. This change involves going from qualitative assessments to quantitative measurements, where precision (up to two decimal places (0.50 mg/L)) takes on a critical role in regulatory compliance.
7.2. Digitization and Data Integrity (Chapter 5.38)
The regulatory focus is no longer limited to water quality, but extends to the reliability of the data that supports it.
Both the FDA and EMA are strengthening requirements related to data integrity, requiring measurement systems to be fully auditable. In this context, the introduction of chapter 5.38 in the Ph. Eur. represents a structural change, aligned with ALCOA+ principles.
The trend points towards the progressive replacement of manual records with continuous online monitoring systems, integrated with digital platforms such as LIMS or validated cloud environments. This approach reduces manual intervention, minimizes errors and improves data traceability throughout its life cycle.
7.3. Sustainability and “cold WFI”
The FDA and the European Pharmacopoeia are actively pushing to reduce the carbon footprint in manufacturing:
- Full acceptance of the RO/UF. Although WFI by membranes (without distillation) has been legal since 2017, the trend for 2026 is its massive standardization. The regulations now focus on requiring a Pollution Control Strategy (CCS) much more robust for these systems, as dictated by the GMP Annex 1.
- FDA approach. Greater scrutiny in the risk-based validation. The FDA does not mandate the use of distillation, but if membranes are used for WFI, expect to see a risk analysis that covers even seasonal variations in tap water.
7.4. Control of emerging contaminants (PFAS)
A growing trend, initially driven by environmental regulation, is the control of emerging contaminants, like PFAS (perfluoroalkylated and polyfluoroalkylated substances)
The introduction of new limits in drinking water, both in Europe and the United States, is beginning to be transferred to the pharmaceutical field, especially in the pretreatment stages.
This context is forcing plants to review their current technologies, particularly ion exchange resins and activated carbon systems, to ensure that they not only meet traditional pharmacopeia requirements, but are also capable of removing these persistent compounds.
Is your water system prepared for the European Pharmacopoeia?
Regulatory changes, digitalization and new technologies are redefining standards in PW, HPW and WFI management.
Assess the status of your facility now and anticipate July 2026 requirements. Our team can help you:
- Analyze the compliance of your current system
- Identify risks in data integrity and microbiological control
- Define an efficient and GMP-aligned upgrade strategy
contact with our specialists for a personalized and no-obligation technical evaluation.