Discussion on Key Points of Quality Management for Pharmaceutical Water Systems

Pharmaceutical water must comply with quality standards—it participates in the entire pharmaceutical production process, including formulation, cleaning, and sterilization. Therefore, pharmaceutical water is a critical component of pharmaceutical production. It is essential to ensure that the design contamination risks in the preparation, storage, and distribution systems of pharmaceutical water are controlled, and that the pharmaceutical water system can consistently provide pharmaceutical water and pharmaceutical steam that meet quality requirements.

Composition of Pharmaceutical Water Systems

The pharmaceutical water system primarily consists of a preparation unit and a storage and distribution system. The pharmaceutical steam system mainly includes a preparation unit and a distribution system, both of which are similar. The preparation unit primarily includes water softeners, purified water machines, high-purity water machines, distilled water machines, and pure steam generators. Its main function is to continuously and stably treat raw water to meet pharmacopoeia requirements or internal corporate standards. The storage and distribution system mainly includes storage units, distribution units, and point-of-use pipeline networks.

Classification of Pharmaceutical Water

From a standards perspective, pharmaceutical water can be classified into pharmacopoeial water and non-pharmacopoeial water. Non-pharmacopoeial water refers to pharmaceutical water not included in the pharmacopoeia but permissible for use in production, such as drinking water, softened water, distilled water, reverse osmosis water, ultrafiltered water, deionized water, and laboratory water. Non-pharmacopoeial water must at least meet drinking water standards. If necessary, it can be used in pharmaceutical production operations, such as cleaning production equipment, as raw material in API production, and laboratory applications. However, the pharmacopoeia stipulates that the formulation of preparations must use water for injection. Therefore, both pharmacopoeial and non-pharmacopoeial water must comply with specified microbial limit standards.

From a usage perspective, pharmaceutical water is mainly divided into bulk water and packaged water. Bulk water, also known as raw water, refers to water used in the pharmaceutical production process. Packaged water, also known as finished water, refers to water produced and packaged according to pharmaceutical processes. The Chinese Pharmacopoeia recognizes bulk water as including purified water and water for injection, and packaged water as including sterile water for injection. The European Pharmacopoeia recognizes bulk water as including bulk purified water, highly purified water, and water for injection, and packaged water as including packaged purified water and sterile water for injection. The United States Pharmacopoeia recognizes bulk water as including purified water, water for hemodialysis, and water for injection, and packaged water as including bacteriostatic water for injection, sterile water for inhalation, sterile water for injection, sterile water for irrigation, and sterile purified water.

Water Production Process Management

Commonly used process waters include:

• Raw water: Water before it enters the water treatment process.

• Purified water: Produced from tap water through multi-media filtration, activated carbon filtration, softener filtration, cartridge filtration, reverse osmosis, and EDI processing.

• Water for injection: Produced by distilling purified water at high temperatures, also known as distilled water.

• Pure steam: Generated by heating purified water at high temperatures.

Preparations Before Water Production

Before starting the equipment, each system should be inspected. The main inspection items for the preparation and storage systems of purified water, water for injection, and pure steam generators are similar:

• Check power supply voltage, tap water supply (water level in the purified water storage tank), industrial steam pressure, and compressed air pressure.

• Inspect all connectors and pipeline connections to ensure no leaks in the pipelines.

• Check the valve status of the storage tank breather.

• Test-run the equipment and check the working status of all components.

Additionally, each system has specific inspection items:

• Purified water system: Check the liquid level in the chemical dosing tank and the status of all manual valves.

• Water for injection system: First, check the valve status of the water for injection storage tank breather and ensure the breather temperature reaches 85°C. Then, test-run the equipment and check the working status of all components.

• Water for injection and pure steam generator systems: Check the pipeline valves for industrial steam and drain condensate from the pipelines.

Water Production Operation Methods

The preparation and storage process of purified water includes:

• Heating the raw water tank, producing water, and circulating.

• Checking the brine tank, adding industrial salt to prepare saturated brine, and completing the dosing record form.

• Checking the caustic tank, adding sodium hydroxide solution, and completing the solution preparation record form.

The preparation and storage process of water for injection can be summarized as:

• Preheating, producing water, circulating, and heat preservation.

The process for producing clean steam is similar, primarily involving:

• Preheating, generating steam, and sampling.

Water System Monitoring and Management

• For the raw water used in production, a full test should be conducted quarterly on samples, including tests for characteristics, pH, and microbial limits.

• For the Purified Water system, the main supply point, main return point, and purified water storage tank should be sampled and fully tested weekly. Other use points should complete a full round of testing monthly, with specific sampling plans for the month drafted by designated personnel. For purified water points in the injection workshop that are unused for over a month, monitoring can be suspended. In this case, the Production Department or QC can submit a planned deviation and apply to suspend use of that point, while QA attaches a "Not for use in production of GMP-related products" sign. Unless under special circumstances, a water point should generally be monitored for three consecutive cycles before use. Product release can only occur after ensuring physicochemical indicators and microbial limit results are qualified. Purified water points suspended for less than a month can be reactivated after normal monitoring. Besides monthly monitoring, daily monitoring tests for the purified water system must be performed, including tests for characteristics, acidity or alkalinity, nitrates, nitrites, ammonia, conductivity, Total Organic Carbon (TOC), non-volatile residues, heavy metals, and microbial limits.

• For the Water for Injection system, the main supply point, main return point, and main product water point should be sampled and fully tested once daily, for conductivity, TOC, microbial limits, and bacterial endotoxins. Other use points should be sampled daily on a rotating basis to ensure a complete round of testing is done weekly. If the WFI system is shut down for more than a week, it must be cleaned and sanitized again. Then, the main WFI point and use points should be monitored for three cycles (testing items as above). The workshop can only use it for producing GMP batches after ensuring conductivity, TOC, and bacterial endotoxins are qualified. Product release can occur after microbial limit results are qualified. If the production cycle is less than a week, ensure all use points are monitored within that cycle.

• For the Pure Steam system, the main point should be sampled weekly and branch points monthly, unless not in use. The daily monitoring items for Pure Steam are similar to those for the Purified Water system, but also include testing for bacterial endotoxins.

Disinfection and Sterilization Management

Pasteurization is a common disinfection method. Within certain temperatures, the lower the temperature, the slower bacteria multiply; the higher the temperature, the faster they multiply. But if the temperature is too high, bacteria die, with different bacteria having different optimal growth temperatures and heat/cold resistance. Pasteurization utilizes the heat-sensitive nature of pathogens, using appropriate temperature and holding time to kill them all. The activated carbon filter in the preparation system generally uses pasteurization (disinfection with 80°C–85°C hot water), while the storage and distribution system typically uses UV disinfection. The following uses the equipment operation at a specific pharmaceutical company as an example to detail system sterilization management.

For the Water for Injection preparation system, if the WFI machine is not frequently started and is shut down for a long time, the storage tank needs to be drained first. Before producing WFI again, the parameter setting interface usually automatically sets the self-sterilization temperature to 121°C, the self-sterilization equipment water inflow rate to 0.3 t/h, and the self-sterilization time to 30 minutes. Starting the "Multi-effect Automatic" function will then initiate self-sterilization immediately upon startup.

When disinfecting the distribution system, first achieve a liquid level of 0.8–1 m for the WFI. Then, click "Distribution Process" for manual operation, click "Transfer Pump" to start circulation, and then click "Heat Exchanger" and select "Disinfection". The disinfection mode is typically set to: disinfection temperature 121°C, disinfection time 30 minutes. The system will then automatically run the disinfection mode.

Red Rust Removal Management

In the pharmaceutical industry, red rust is generally a direct product of metal corrosion. It can lead to system component damage, pipeline leaks, filter clogging, and potential heavy metal contamination of the pharmaceutical water quality. Therefore, regular cleaning and disinfection of the Purified Water and Water for Injection systems, along with proper documentation, is necessary to remove microorganisms attached to system surfaces and prevent red rust formation. Once red rust appears, pharmaceutical companies must address it seriously. If red rust appears on the tank body, relevant parties should be contacted immediately for passivation treatment. If red rust appears on pipelines, they should be replaced promptly.

Water Production System Maintenance Management

• For the Purified Water system:

  • Clean the tap water tank annually.

  • Disinfect and remove sediment from the raw water tank every two months.

  • Perform pasteurization on the purified water storage tank and distribution system every two months.

  • Perform surface cleaning of the raw water tank monthly.

• For the Water for Injection system:

  • Regularly inspect the WFI tank, instruments, gauges, and clean inverter surface dust, cleaning promptly.

  • Inspect all pneumatic valves and cabinet ventilation fans, promptly removing dust inside electrical cabinets.

  • Inspect and calibrate sensors (e.g., temperature sensors, pressure gauges, pressure sensors, conductivity meters, flow meters).

  • Inspect and calibrate safety valves.

  • Inspect/replace breathers.

  • Check purified water pumps and WFI circulation pumps for noise, bearings, and water seals.

  • Inspect heat exchangers for scaling and arrange cleaning.

• For the Pure Steam system:

  • Regularly inspect/clean safety valves, heat exchangers, pure water pumps, instruments, gauges and sensors, power switches and signal indicators, DC power supplies, various electrical components (e.g., AC contactors, relays), PLCs, recorders, HMIs, various pneumatic valve components, power wires inside control cabinets, steam traps, and equipment scale.

  • Promptly inspect/replace pump mechanical seals and motor bearings.

  • Check pipelines for leaks.

  • Check equipment grounding/insulation.