Performance Qualification Protocol for Water for Injection (WFI) System : Pharmaguideline

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Performance Qualification Protocol for Water for Injection (WFI) System

Learn the validation procedure and how to write the validation protocol for water for injection system in pharmaceuticals.


       The objective of this protocol is to qualify and certify the performance of the Water for Injection generation, storage and distribution system.

2.0  SCOPE:

      This protocol is applicable to water for injection generation, storage and distribution system.


Quality Assurance: Preparation, Review and Approval of Performance Qualification Protocol.
Production: Review of Performance Qualification Protocol and coordination with QA, Q.C, and Engineering department.
Quality Control: Review of Performance Qualification Protocol, Sampling & Analysis of WFI and coordination with QA, Engineering and Production department.
Engineering: Review of Performance Qualification Protocol and coordination with QA, Q.C and Production department.


•  Change in process parameters.
•  Changes in design or major maintenance.
•  Change in critical components such as pumps, storage tank, pipelines etc.


5.1 Multi Column Distillation Plant (MCDP):

5.1.1 WFI generation Plant Produces Pyrogen-free water and It engrosses with Liquid-Vapour – Liquid Phase change to produce very high purity water. It removes the impurities at sterile temperature without using any filtration medium.
5.1.2 Equipments is based on “Falling Film Evaporator” Principle, which is most reliable method to Produce WFI.
5.1.3 The Unit designed to remove microbial contamination by three-stage Separation. Number of effects is connected in series. Each effect has a innermost evaporator (shell & tube heat exchanger), an intermediate separator and outer columns. Source of energy for the first effect is Boiler Steam and the remaining effects use the intrinsic heat to supplement consumption needs of heating energy.
5.1.4 Feed water (Purified water) is preheated by waste heat recovery method and enters the first effect from tube side. Specially designed distribution plate ensures the water falls down the tube as a “Thin film”. The falling film is heated with plant steam and causing it to a instant flash evaporation. This flash evaporation helps the steam to leave behind the heavier particles or droplets (First stage of Separation). This transformation from water to steam significantly increases the velocity as it approaches the bottom of the column with high pressure.
5.1.5 This Vapor as it moves outside the tube, is forced to change its direction to a 180° turn. This directional change induces the separation of large water droplets (Secondary Separation), which falls into the bottom of the column, where they are collected with excess feed water that has not evaporated.
5.1.6 As the Steam moves upwards, the spirals provided on the shell of evaporator force the steam to move in a circular path. The resulting centrifugal action forces the remaining microscopic droplets and impurities including the Endotoxins to the outer surface, which then gets blow down through the windows provided on the separator (Third stage Separation). The resulting steam is pure pyrogen free sterile steam.
5.1.7 Thus Produced Pure steam becomes the source stream for next effect, un-evaporated water becomes the feed water and this process is repeated in all the remaining Effects. Pure steam Condenses as WFI in each effects and WFI along with the Pure Steam from the last column is taken to the condenser where it is cooled to 95°C by using cooling water.

5.2 Water for Injection storage tank and close circulation loop:
5.2.1 The Water for Injection shall be stored in jacketed and SS storage tank, containing SS 316 L contact part and SS 304 noncontact Part. 
5.2.2 Spray ball provided at the centre nozzle (loop return) on the manhole for continuously wetting all the contact parts on the top surface of the tank including the manhole internal surfaces.
5.2.3 Hydrophobic filter of 0.2 micron PTFE, 1 x 10" with electrical heater & SS 316L Jacketed Housing vent filters is provided on top of the tank, function of this vent filter is to prevent entry of airborne bacteria to the system and to prevent the development of dangerous levels of pressure or vacuum in the tank during all phases of operation.
5.2.4 Distribution of Water for Injection to all users points are provided in closed circulation loop. Normal minimum velocity of WFI in loop is 2.5 m/s and during peak load minimum velocity 1.2m/s shall be maintained. The water quality parameters such as Total Organic Carbon, Conductivity and temperature are monitored online.


6.1 Instrument & Material:
6.1.1  Calibrated pH & Conductivity meter.
6.1.2  Reagents and standard solutions should be freshly prepared.
6.1.3  Hand Gloves.
6.1.4  LAL Reagent
6.2  Safety precautions: Use personal protective equipments (PPE) during the sampling.

6.3 Water quality monitoring:
6.3.1 Sampling frequency for Water for Injection :  Phase – I ( Investigational Phase ):
•  The duration of this phase will be one month.
•  Analyze the samples as per the specifications.
•  If the limits are exceeded or water quality is not meeting the acceptance criteria, investigation shall be performed, corrective action shall be taken, and period of performance qualification should be extended as appropriate.
•  After completion of phase-I study, report & trend analysis shall be prepared, reviewed & approved by concern authority, if found satisfactory.
•  In case any deviation is observed during the study, the same is to be reported in deviation Report.  Phase - II (Verifying Phase ):
•  The Phase-II will start after satisfactory completion of Phase-I. The duration of this phase will be 21 days.
•  Analyze the samples as per the specifications.
•  If the limits are exceeded or water quality is not meeting the acceptance criteria, investigation shall be performed, corrective action shall be taken, and period of performance qualification should be extended as appropriate.
•  After completion of Phase-II study, report & trend analysis shall be prepared, reviewed & approved by concern authority, if found satisfactory.
•  In case any deviation is observed during the study, the same is to be reported in Deviation Report.  Phase - III ( Verifying Long Term Control ):
•  Phase –III will run for 1 year after satisfactory completion of Phase-II. The sample locations, sampling frequencies and tests will be reduced based on the results obtained during Phase – I & II. During reduced sampling frequency, all sampling points of WFI shall be covered within a week time in rotation.
•  During Phase-III study, the results will be reviewed after every two months till the end of Phase-III.
•  At the end of Phase -III, all results shall be reviewed and based on results conclusion shall be drawn.
•  Any deviation, observed during the study, shall be reported.

6.3.2 Tests to be performed for Water for Injection:
The following parameters shall be tested:
1. Description
2. Conductivity ( At 25 °C )
3. Bacterial Endotoxins Test
4. Microbial limit test
5. Acidity or alkalinity
6. pH
7. Ammonium
8. Calcium and magnesium
9. Heavy metals
10. Chlorides
11. Nitrates
12. Sulphates
13. Oxidisable substances
14. Residue on evaporation
6.4 Documentation:
The performance qualification protocol will be signed by respective individuals and the effective date of the protocol will be given after the approval of the protocol by Head Quality Assurance or designee. The filled reports shall be attached with validation report.

Sr. No.

Acceptance criteria

Clear, colorless and odorless liquid.
Conductivity At 25°C
NMT 1.3 mS/cm
Bacterial Endotoxins
NMT 0.25 EU/ml
Microbial limit test
Total bacterial  count - Less than 10 cfu / 100 ml and Total fungal count - Should be Nil
Escherichia coli, Salmonella spp., Pseudomonas aeruginosa, Staphylococcus aureus, Shigella, Clostridia, Enterobacteriaceae should be absent.
Acidity or alkalinity
No red or blue color produced.
5.0 to 7.0
NMT 0.2 ppm
Calcium and magnesium
A pure blue color is produced
Heavy metals
NMT 0.1 ppm.
The solution shows no change in appearance.
NMT 0.2 ppm
The solution shows no change in appearance.
Oxidisable substances
The solution remains faintly pink
Residue on evaporation
NMT 0.001 %

The results obtained after execution of the protocol will be presented in the validation report. All results will be compared against the acceptance criteria. Any deviation failure to meet these specifications will be duly documented in the deviation form and deviation log provided along with this protocol and will not be subject to the provisions of the SOP of Deviation Control. A deviation indicates variance from the acceptance criteria, however, does not necessarily mean that the qualification as unacceptable. 

During execution of this protocol, if any deviation is noticed, the person executing the protocol initiates a deviation report and provides the detail description of the deviation. The investigation may be performed to identify the root cause for the deviations or failures and corrective action will be taken to minimize such deviations or failures in the future. Photocopy of all relevant analytical test certificates shall be attached to the Validation report.

9.0  Conclusion: Conclusion will be drawn after completion and evaluation of results.
Indian Pharmacopoeia
British Pharmacopoeia
United State Pharmacopoeia
WFI Specification

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