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Information in this post shall also be available on the Water Systems Validation page, a child page of Validation.

 

Water Systems Validation

See Water Types for more information regarding types of water and their systems

In 2016, The European Directorate adopted their new chapter for Water for Injection (WFI), allowing the use of reverse osmosis (RO) in addition to water from distillation as long as the water quality is equivalent. With RO, there is a potential for microbial break through, or even contamination from microbial by products or the accumulation of biofilm. To detect these issues early, a system must be developed with a robust testing protocol utilizing conductivity and total organic carbon levels (TOC).

The conductivity of WFI must be less than 1.3 microSiemens per centimeter (mS/cm) at 25 °C. All require bacterial levels to be less than 10 colony-forming units per 100 milliliters (cfu/100 mL) and endotoxin to be less than 0.25 international units (IU)/mL. Total organic carbon (TOC) must be less than 0.5 mg/L for United States, Europe, and Japan. Europe and China additionally require less than 0.2 ppm for nitrates.

Commissioning the System

PDA Technical Report No. 4, (TR 4) Design Concepts for the Validation of Water for Injection System

System determined by type of water to be used. Some parenteral and some inhalation products have a concern in regards to pyrogens. 

USP WFI is defined as water purified by distillation or reverse osmosis, is pyrogen-free, contains no added substances, and meets the requirements for Purified Water USP with the exception of bacteriological purity.

When designing the system, each subsystem must be developed with specifications and procedures.

• In plant pretreatment systems
• Distillation unit (or RO, or both)
• Water holding system
• Distribution network

Reports from incoming water supply (municipal reports or testing on private supply) are used to determine quality and variability of incoming water supply. These documents are of use when establishing targets for water quality, and of use to select any pretreatment equipment to change the characteristics of the incoming water (hardness, particulates, organic chemicals). Determine if incoming water will have seasonal variation or changes of supply due to drought or other environmental factors. Ensure notification by water supplier of any changes. 

Filtration:

• Sand Filters
• Charcoal Filters (will remove any chlorination treatment of potable water)
• Water Softeners
• Deionizers

Ensure risk assessment for each type of filtration, with procedures to mitigate and/or preventative maintenance.

Reverse Osmosis vs. Distillation:

Reverse Osmosis filters water through a series of membranes (membrane filtration). Water hits membranes at a tangent, and ion heavy water is rejected. Efficacy of the system is determined by requirements and budget. Multiple passes of water is conducted, followed by electrodeionization (EDI) and ultrafiltration (UF).

Pro- Performed at ambient conditions, can take up less space, lower costs.  Purified water systems using RO can be retrofitted with UF terminal filter to provide WFI water.

Con- Water must be pre-treated to remove chlorine and ammonia. Risk of bacteria growing on membranes or in storage or distribution systems. Downstream sanitization and inline monitoring required.

Distillation utilizes state changes (boiling, condensation). The two types in pharmaceutical manufacturing facilities usually used is multiple-effect distillation (MED) and vapor compression distillation (VC). Water containing impurities cool faster and run back into the distillation equipment as the purer steam advances along the evaporator to condensation. For MED, this process is repeated multiple times.

Pro- Water is hot, can be used as sanitizing agent

Con- Water must be pre-treated to remove chlorine and other contaminants that can damage the equipment.

High purity water may cause corrosion, requiring proper welding and a smooth finish weld to reduce any locations for corrosion or microbial build up.

Storage tanks- determine capacity per rate of use, frequency of flushing and sanitizing internal surfaces. Vent filters are required with hydrophobic bacterial retentive filters to control microbial quality of air entering the tank. A heat jacket may be equipped.

Pumps should be periodically checked for function, preventative maintenance on valves and seals. When not in operation, static water may be an issue.

Monitoring equipment is used in the system to determine water levels and temperature. These must be calibrated and maintained.

USP WFI is usually produced in a continuous circulating system at a high temperature to minimize microbial growth. WFI held at ambient temperature must be dumped or diverted to non WFI use after 24 hours.

Distribution loops utilize two pumps in parallel and in alternation to maintain positive loop pressure. A frequency converter controlled by a flow rate transmitter keeps the pressure stable when multiple points are used. Loops utilize auxiliary components such as overpressure valves, check valves, diaphragm valves, UV for sanitation, and heat exchangers. For WFI, loops are cooled prior to use.

When considering piping: velocity, slopes, deadlegs, temperatures, and sampling points.

Rouging: film of iron oxides and hydroxides – monitor

Pure steam systems rouge quickly, pass through steel mesh before process use.

System Qualification

Validation of system by challenge is not possible in water systems, as the introduction of organisms is undesirable. A robust testing and monitoring system at checkpoints is utilized to ensure system operation.

Each System component requires defined quality and performance criteria for its individual function. A validation report includes a description of the system and its individual components.

WFI water must be sterile, with less than 10 CFU/100ml. All microbial samples must be greater than 100 ml. Endotoxin limits are generally less than 0.25 EU/ml. TOC content must be less than 0.5 mg/L. Products distributed to EU or China require less than 0.2 ppm for nitrates.

Design Qualification

• Include information about all components
• Schematic diagram of:
  • mechanical components/equipment
  • electrical
  • water flow
• Define needed purification
• Define safety controls
• Define control devices, indicators, and alarms
• Specify sampling plans and points for microbial and chemical testing, method of data analysis.
• Specify sanitation methods
• Specify temperature controls
• Ensure piping – (hot and ambient near each other requirements)

 

Installation Qualification

• Develop blueprint/schematic (usually done during DQ)
• Develop system checklist for critical items (pumps, valves, heat exchangers, more), list specifications, and designate items for calibration program.
  • Have a list (may be separate) with: Description, Mfg, Model, Serial, Date purchase/install, location, replacement parts list.
  • Separate List with control instruments including mfg, model, serial and identifying codes (thermometers, thermocouples, switches, timers…)
• Ensure correct installation per schematic
• Ensure correct materials and smooth welding
• Write prospective SOPs for operating, cleaning, sanitizing, and maintenance
• Ensure all documentation for all equipment is available and in designated location.
• Clean and rinse all equipment and pipes. Passivation of stainless steel. (document procedures and test rinse water for detergents, solvents, or particulates)

Operational Qualification

• Use schematic and checklist to determine control functions.
• Each control function tested and meet specifications listed
• Total system checks using temperature sensors, conductivity meters, flow meter. Check against manufacturer parameters.
• RO/Distillation equipment performance checked and recorded for output, blowdown, temperature, flow rate/pressure. Flow must be at least 90% of rating.
• Storage tank- temperature, vent filter (temperature constant monitoring). Test automatic valve set ups for drain. Test if drain if falls below temperature. 

Performance Qualification

Written procedures regarding sampling and monitoring. Documentation and schematic of all sampling sites. Frequency and methods of sampling must be detailed.

Maintenance Logs for each piece of equipment and test/calibration equipment

Sampling Logs including all sampling locations, samples must be recorded, dated, and signed (both log and sample)

Phase 1

Sampling and testing daily for 15-30 days to monitor system: raw water, sampling after each step (ro/still outlet, UF outlet, storage vessel, distribution line, each port), chemical and microbial testing: Viable organisms, pyrogen/endotoxin, temperature, conductivity, particulates, TOC, Appearance, pH, Odor, resistance, chloride, sulfate, heavy metals, ammonia, calcium, carbon dioxide, oxidizable substances.

• finalize all procedures as pertain to operation, cleaning, sanitizing, preventative maintenance.
• Use testing data for profile for normal conditions. Finalize alert and action levels.

Phase 2

Similar to phase 1,  however water may be used for manufacturing during this phase.
Demonstrate water system produces required water quality and quantity while SOPs are being followed.

Phase 3

One year, water can be used for manufacturing during this phase.
frequency of sampling can be reduced.

 

Seasonal Trending

Changes to municipal supply (does water source change if drought?)

Requalification

Annual comparison to system to identify changes.