What are the Requirements for GMP-compliant Water Systems?

Water systems for pharmaceutical manufacturing must comply with a range of regulations. The required water qualities, treatment and storage, as well as distribution, must be taken into account.

In pharmaceutical manufacturing, three main water qualities are used:

• Drinking water
• Purified water (PW)
• Water for injection (WFI)

The exact quality and testing parameters for PW and WFI water qualities are described in pharmacopoeias. The most important of these are the European Pharmacopoeia (EP) and the United States Pharmacopeia (USP). Key testing parameters include, for example, conductivity, Total Organic Carbon (TOC) and the bacterial count (CFU). The 'Guideline on the quality of water for pharmaceutical use' issued by the European Medicines Agency (EMA) specifies which water quality is to be used for which type of pharmaceutical manufacturing or for which manufacturing steps. For example, the manufacture of non-sterile dosage forms may be carried out using PW. The final cleaning of manufacturing equipment used to produce sterile medicinal products, on the other hand, must be carried out using WFI. WFI is also used for the manufacture of sterile medicinal products.

According to pharmacopoeia specifications, the starting point for the production of pharmaceutical water (treatment) is drinking water. This applies to both the production of PW and WFI.

A) Production of PW

The design and selection of the necessary components for a purified water treatment plant are determined by the quality of the drinking water used. The first stage of the process is typically softening using cation exchange resins. The main component of the treatment is often reverse osmosis (RO) as the core technology, which can remove 95-99% of substances. This is followed by a second reverse osmosis stage (double RO) or electrodeionisation (EDI) to ensure compliance with conductivity requirements. For critical PW applications, ultrafiltration (UF) may also follow.

B) Production of WFI

In the past, WFI was mainly produced by distillation. Since the amendment to the European Pharmacopoeia in 2017, WFI can also be produced in Europe using membrane processes, i.e. cold - without heating.

In the cold production of WFI, softening with RO (to reduce particles, ions, TOC, endotoxins and microorganisms) and subsequent EDI is generally also employed. Final ultrafiltration (UF) is mandatory for WFI. The UF stage is the 'quality-determining step' here, as it can effectively remove endotoxins and microorganisms.

Once the water has been produced to the required quality, it is fed into a storage tank and distributed to the individual process consumers via a looped piping system. Naturally, the quality achieved must be maintained throughout this process.

A crucial aspect of both the design and operation of water systems is the avoidance of stagnant water. Stagnant water is problematic, as continuous monitoring of conductivity and TOC is generally difficult. Furthermore, maintaining positive overpressure on the pure side is often not possible, which can lead to microbiological contamination.

For this reason, PW and WFI water systems must always be kept in operation or circulated. So-called dead legs, in which there is no turbulent flow, must be avoided.

The so-called 3D rule applies to this design aspect. It states that the length of a dead space (or branch) L should be less than three times the diameter of the branch pipe. This requirement can be found, for example, in the ISPE Baseline Guide Water and Steam and in Annex 3 of the WHO document TRS 929. Further design criteria for a GMP-compliant water system include the material and its surface (internal surfaces in contact with water). The suitable material is 316L grade stainless steel, with a surface roughness of Ra <= 0.8 µm.

The suitability of the system for the production of pharmaceutical water is demonstrated through qualification. This involves testing the design, installation and function of the systems. In the final step, performance is then verified under operating conditions (Performance Qualification, PQ). It is common practice to carry out the PQ in three phases. These can also be found in the still-valid FDA Guide to Inspections of High Purity Water Systems from 1993.

Phase 1 - Monitoring under operating conditions

Duration: approx. 2 weeks
Objective: To demonstrate that the water system operates stably during normal operation.
Testing scope:

• Daily microbiological sampling at all sampling points
• Chemical analysis (conductivity, TOC)
• Monitoring of operating parameters (temperature, flow rate, disinfection cycles)
• Demonstration that cleaning/disinfection are effective and that the system remains stable even under varying operating conditions
• Use of the water for production (however, the manufactured product is generally subject to quarantine until the end of Phase 2)

Phase 2 - Monitoring under realistic operating conditions

Duration: 2-4 weeks
Objective: Confirmation of stability over a longer period with realistic fluctuations (e.g. weekends, shift work).
Test scope:

• Continuation of microbiological and chemical tests, test frequency as in Phase 1
• Assessment & decision on whether there are worst-case points in the system and data- and risk-based creation of the routine sampling plan

Upon successful completion of PQ Phase 2, the water is generally granted approval for GMP production, provided all specifications have been met.

Phase 3 - One-year operation

Duration: typically 1 year
Objective: To confirm system robustness across all seasons under real operating conditions. This PQ Phase 3 is intended to test the PW and WFI systems for unacceptable seasonal fluctuations.
Test scope:

• Microbiological and chemical analyses in accordance with the established routine monitoring plan
• Evaluation of seasonal effects, consumption profiles, maintenance cycles
• Trend analyses of all quality and operational data, including confirmation of the predefined sanitisation cycles
• Normal use of the water for production

An important aspect is the sanitisation of the water system, which reduces bacteria and thus keeps the system under microbiological control. To this end, both the water production and the storage/distribution system must be designed to be sanitised.

Sanitisation of the production plant is usually carried out thermally, i.e. by cyclically heating the system to over 65°C. The required duration and frequency depend on the system's design and usage and are determined during the design phase and confirmed during qualification.

The storage and distribution system, on the other hand, can be sanitised thermally or chemically, e.g. with ozone. When sanitising with ozone, a concentration of, for example, 50 ppb is used for a short period (1-2 hours). For longer sanitisation periods (> 6 hours), a concentration of >= 20 ppb may be sufficient. From a technical perspective, it is important to note that the materials used - particularly plastics - must be able to withstand the oxidative stress caused by ozone.

Thermal sanitisation of the storage and distribution system can be carried out intermittently - similar to the production systems. However, continuous thermal sanitisation is particularly reliable and recommended for WFI - whereby the WFI is maintained in the system at over 65°C 24 hours a day.

Cold systems (cold PW and WFI production and cold storage) are somewhat more challenging when it comes to sampling, as the outlet side of the sampling valves is highly susceptible to contamination. For this reason, special sampling procedures often need to be defined for cold systems (e.g. flame-sterilising the outlet side of the valves or filling with disinfectant).

 Please also see a selection of training courses on technical issues in the GMP environment on the ECA GMP Compliance website.