|No. of Pages|
|Reference Protocol No.|
1.0 Protocol Approval
2.2 Purpose and Scope
2.4 Qualification Team
3.0 Traning Record
4.0 Performance Qualification Requirements
5.0 System / Equipment Description
5.1 System / Equipment details
6.0 Performance Qualification Procedure
7.0 Re- Validation Critaria
8.0 Acceptance Criteria
9.0 Qualification Report
10.0 Observed Deviation
11.0 List of Exhibits/Annexure
11.1 List of Exhibits
11.2 List Annexure
12.0 Reference Documents
- Protocol Approval
This is a specific protocol for Performance Qualification of Water for Injection generation, Storage, Distribution System.
This protocol has been approved by the following:
Final approval has been given by the following:
(Head – QA)
To establish the methodology for the Performance Qualification of WFI Generation, Storage and Distribution system (ID.NO: ______________), which produces pyrogen free, water for injection, used as a Sterile products manufacturing facility.
Purpose and Scope
The purpose of this Protocol is to establish the performance Qualification of WFI generation, Storage and Distribution system to:
- Demonstrate that WFI System shall perform reproducibly and consistently with in its full dynamic range of operation according to Functional / Manufacturer’s / In house specifications.
- Document the initial performance of the WFI System for future reference.
- Assure that the WFI System performance is adequate to support the method/methods for which the system is intended.
- Assure the accurate and precise results/observations of the substances being examined are recorded.
- Protocol / Report Preparation: Officer or above QC / QA
- Protocol / Report Checking: Manager QC / Nominee
- Execution of Qualification Activity: Officer or above QC / QA
- Protocol / Report Approval: Head QA
- Final Approval: GM formulation / Head QA
The Production and Engineering Department shall be responsible for checking the operation. The Quality Control shall be collecting the sample from the sampling points according to the sampling plan and Quality Control shall carry out the tests as per the specifications and respective test procedures. The Quality Control shall prepare the data trend for all the three phase of validation study. The summary report of the Performance Qualification shall be prepared by Quality Assurance Department. Separate reports will be prepared for phase-I, phase-II, and phase-III studies respectively.
- Qualification Team
- User Department Officer / Executive
- Officer / Executive QA
- Manager QA / QC
- Training Record
The purpose of the training is to familiarize the trainees with the principle of working & technical specifications of WFI System as well as overall strategy of Performance Qualification of the WFI Generation, Storage and Distribution System.
This Training is related to the Water for Injection generation, storage and distribution system and being imparted to the people involved in the WFI water system validation.
The following topics to be covered during training:
- Principle and operating of Water for Injection system.
- Technical specifications of the system components.
- Overall strategy of Qualification process.
- General precautions / guidelines to be followed during qualification.
- Training is given as per SOP Title: SOP on cGMP Training
- Training record have been attached with the report
Performance Qualification Requirements
Following reagents/ chemical/standards shall be required for the Performance Qualification of Water for Injection system
- Bottles for Sampling.
- All test solutions.
System / Equipment Description:
- Equipment Identification Number
- Name of the system/Instrument
- Manufacturer’s Name
- Purchase Order Number
- Date of Installation
The Water For Injection System Still is working on the Principle of inters stage heat exchange (Reuse of energy) drastically reduce the consumption of heat energy and cooling water. Thus enable to produce large- scale of Pyrogen free sterile water for injection. The Distillation Column operates at different pressure and temperature making it possible to transfer the energy in process forward column to column.
Brief Instrument Description:
Water for Injection System produces pyrogen free, sterile water for injection which meets the requirements of the international pharmacopeias including USP, BP, and IP. It operates on the distillation as a unit process. Sterile water generation engross with Liquid-vapor-liquid phase change to produce very high purity water.
Water for Injection system works on “Falling Film Evaporator” principle. It employs high temperature which assures constant sterile water.
The unit design 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 column. Source of energy for this effect is boiler steam & the remaining effects use the intrinsic heat to supplement consumption needs of the heating energy.
Feed water is pre heated by waste heat recovery method and enter 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 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.
This vapor as it moves outside the tubes is forced to change its direction to a 180º turn. This directional changes induces the separation of large water droplets (secondary separation), which fall into the bottom of the column, where they are collected with excess feed water that has not evaporated.
As the steam moves upwards, the spirals provided on the shell of the evaporator forces 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).
Unevaporated water becomes the feed water & this process is repeated in all the remaining effects each working at lower temperature & pressure than the one preceding it. Pure steam condenses as WFI in each effects & WFI along with the pure steam from the last column is taken to the condenser where it is cooled to 95º C by using cooling water.
Plant operates on PLC system. PLC system ensures efficient working of plant under favorable conditions. In case of violation of any critical condition, plant will automatically stop & give audio-visual signal to operator. When the problem gets solved, plant will start automatically.
System has unique feature of purging which remove water containing pyrogen and other impurities and keep concentration of impurities to minimum level.
So, WFI produced from each column except first column will be collected at bottom of the column & transferred to cooler. Steam, which is produced in final column, will also be taken to cooler, which will convert into WFI.
Brief Description of Distribution System :
Control of WFI distribution loop and WFI storage tank will be through common PLC panel. Distribution of WFI through various user point provided in the loop system. WFI is generated using Multicolumn and stored in WFI storage tank at 85°C to 90°C. It is pumped into distribution loop using centrifugal pump. One stand by pump is also provided. All piping is having Armaflex insulation with SS 304 cladding below false ceiling and with aluminum foil above false ceiling.
The return loop to the WFI tank is having following instrumentation and control.
- Flow Indicator and controller: – It will indicate flow rate in the return line and will control the minimum return flow rate to WFI tank using VFD of circulation pump.
- Conductivity sensor and controller: – Conductivity sensor will sense conductivity of WFI coming in return loop and if conductivity is beyond the set point, it will drain all WFI.
- Temperature sensor, Transmitter and Indicator: – It will sense temperature of WFI in return line and will indicate same.
Performance Qualification Procedure
- The following procedure has been used for performance qualification of Water for Injection generation, storage and distribution system:
- Water for Injection System was checked for completion of the operational qualification activity.
- The Performance Qualification of water system is proposed to be carried out in three phases
Performance Qualification Plan & Rationale:
- Phase-I – extensive sampling from Generation points & usage points for 1 month
- Phase-II – extensive sampling from selective generation & all usage points for 3 months
- Phase-III – routine sampling from usage points on rotation basis, for 8 months
The phase-I study shall be done as per procedure mentioned below. The observation of the study shall be recorded as per the format provided in Exhibit-01.
The data sheets shall be attached date wise in Annexure-02.
After completion of phase-I studies the graphical representation of the data of all the parameters shall be done individually and should attached in Annexure-04.
Phase – I: (For a period of 1 month)
The performance qualification of Water for Injection System shall be started, when all the equipment and piping of WFI system had been verified to be installed properly and operating correctly.
Phase-I of the performance qualification of Water for Injection System included extensive sampling of WFI, from various points along with all the usage points of the distribution loops . The phase-I sampling shall be carried out for a period of 1 month.
During this phase water samples from all generation / usage points shall be analysed and monitored for compliance to the pre-determined specifications.
After successful completion of Phase-I of the performance qualification, the Water for Injection System should be cleared for usage of WFI water in manufacturing operations. Purpose of Phase-I qualification is to stabilize the operating parameters. Conclusions have been described in a summary form.
- The phase-II studies shall be done as per procedure mentioned below. The observations of the study shall be recorded as per the format provided in Exhibit-01.
- The data sheets should be attached date wise in Annexure-04.
- After completion of phase-II studies the graphical representation of the data of all the parameters shall be done individually and shall be attached in Annexure-05.
Phase – II: (For a period of 3 months)
Phase-II of the performance qualification shall be commence, after successful completion of Phase-I. Purpose of Phase-II qualification is to monitor the operating parameters. The objective of Phase-II is also to demonstrate that system is producing desired quality of water, on a consistent basis, when operated in conformance with SOP established at the end of Phase-I. Conclusions shall be mentioned in Summary report.
During Phase-II, WFI water samples shall be collected from various Sampling Points in generation system as mentioned in sampling plan and Usage Points on a Daily basis. Phase-II of the performance qualification of Water for Injection System include extensive sampling of WFI water from all sampling points in the Water for Injection System & usage points of the distribution loops on daily basis. Phase-II sampling carried out for a period of 3 month. Water samples from the all the usage points shall be analysed and monitored daily, for compliance to the pre-determined specifications.
After successful completion of Phase-II of the performance qualification, the Water for Injection shall be cleared for Phase-III.
- The phase-III studies shall be done as per procedure mentioned below. The observations of the study shall be recorded as per the format provided in Exhibit-01.
- The data sheets should be attached date wise in Annexure-06.
- After completion of phase-III studies the graphical representation of the data of all the parameters shall be done individually and shall be attached in Annexure-07.
Phase – III: (For a period of 8 months)
- Phase-III of the performance qualification shall be commencing, after successful completion of Phase-II. Purpose of Phase-II qualification is to monitor the operating parameters. The objective of Phase-III is also to demonstrate that system is producing desired quality of water, on a consistent basis, when operated in conformance with established SOP and does not have any seasonal variation through out the Phase-III study to collect the robust data. Conclusions shall be mentioned in Summary report.
- During Phase-III, WFI water samples shall be collected from various Sampling Points in Water for Injection System as mentioned in sampling plan and Usage Points on a weekly basis. Phase-III of the performance qualification of Water for Injection System include extensive sampling of water from various points in the WFI water generation system & all the usage points of the distribution loops on weekly basis. Phase-III sampling carried out for a period of 8 months. Water samples from the all the usage points shall be analysed and monitored weekly, for compliance to the pre-determined specifications.
- Specifications of Water for Injection:
|S. No.||Test Parameter||Specification||STP/ GTP code|
|A. Chemical Analysis|
|1.||Description||Clear colourless, odourless and tasteless liquid|
|2.||pH (at 25°C)||Between 5.0 to 8.0|
|3.||Conductivity (at 25°C)||NMT 1.3 µS / cm|
|4.||Ammonium||NMT 0.3 ppm|
|5.||Calcium||No turbidity observed|
|6.||Chlorides||NMT 0.50 ppm|
|7.||Sulphates||No turbidity observed|
|8.||Total Organic Carbon||NMT 500 ppb|
|9.||Oxidisable Substance||The solution remain faintly pink|
|10.||Carbon Dioxide||The solution should remain clear|
|B. Microbiological Analysis|
|1.||Total Aerobic Microbial Count (TAMC)||NMT 10 cfu / 100 ml
|2.||Bacterial Endotoxin Test||NMT 0.125 EU / ml|
6.7 Sampling Plan & Frequency
|S. N.||Name of the Sampling point||Specification Compliance||Sampling point No.||Room No.||Phase – 1 Sampling frequency||Phase – 2 Sampling frequency||Phase – 3 Sampling frequency / Day|
|A||WFI sampling points in Generation system|
|1.||After Column II||As per WFI||WFI – 01||NA||Daily||
|2.||After Column III||As per WFI||WFI – 02||NA||Weekly|
|3.||After Column IV||As per WFI||WFI – 03||NA||Weekly|
|4.||After Column V||As per WFI||WFI – 04||NA||Weekly|
|5.||After WFI Generation||As per WFI||WFI – 05||NA||Weekly|
|6.||Storage Tank||As per WFI||WFI – 06||NA||Daily|
|B||Usage points in WFI Distribution loop system|
|7.||Garment Washing Room||As per WFI||WFI – 07||
|8.||Equipment Washing and Sterilization Room||As per WFI||WFI – 08||Weekly|
|9.||Vial Washing Room||As per WFI||WFI – 09||Weekly|
|10.||Before Bung Processor||As per WFI||WFI – 10||Weekly|
|11.||Return Loop||As per WFI||WFI – 11||Daily|
Evaluation of test results shall be done by comparison against the standard criteria.
- Alert level and action level shall be established on the basis of Phase-I and Phase-II data.
- Alert levels are levels or range that, when exceeded; indicate that a process may have drifted from its normal operating condition.
- Alert levels constitute a warning and do not necessarily require a corrective action.
- “Alert Level = Max. Count + 2 X Standard Deviation”
- Action levels are levels or range that, when exceeded, indicate that a process has drifted from its normal operating range. Exceeding an Action level indicates that corrective action should be taken to bring the process back into its normal operating range).
- “Action Level = Max. Count + 3 X Standard Deviation”
- Deviation observed during the Phase-I, Phase-II & Phase-III of performance qualification shall be noted.
Re – validation Criteria:
- Performance Qualification of WFI Water System to be revalidated on:
- Any major modification in the existing system including distribution loop since purchase, which potentially could affect flow rates storage, delivery, sampling or water quality, or significant change in the operational parameter.
- If the system is found to be malfunctioning after any deviation / after any major breakdown maintenance.
- Relocation of the system.
- Performance qualification shall be considered acceptable when all above requirements of this protocol has been fulfilled and all the parameter is functioning as per the design specifications and as per manufacturer’s recommendations.
- The performance qualification report shall consist of a summary document, in narrative form, which shall briefly describe the activity performed along with the observations recorded in relevant exhibits.
- This report shall also include the related documents and attachments / annexure which were completed at the time of qualification activity.
|Sr. No.||Page No.||Point No.||Observed Deviation||Deviation Reported By||Deviation Approved By||Corrective Action Taken||Justification of Corrective Action||Corrective action taken and justification given by|
List of Exhibits / Annexure
- List of Exhibits
|Exhibit No.||Exhibit Title||No. of Pages|
|01||Data sheet for PQ test results of WFI Water|
|Total No. of pages|
- List of Annexures
|Annexure No.||Annexure Title||No. of Pages|
|02||Data sheets of Phase-I|
|Graphical representation of Phase-I results|
|03||Data sheets of Phase-II|
|Graphical representation of Phase-II results|
|04||Data sheets of Phase-III|
|Graphical representation of Phase-III results|
|Total No. of pages|
- Design Qualification
- Installation Qualification
- Operation Qualification.
- United States Pharmacopoeia.
- Indian Pharamcopoeia.
(Exhibit – E01 ) Data Sheet for PQ Test Results of WFI Water
Sampling Point No.: Phase: I/ II/ III
|Test Parameters (ê)||Results|
|pH (at 25°C)|
|Conductivity (at 25°C)|
|Total Organic Carbon|
|Total Aerobic Microbial Count (TAMC)|
|Bacterial Endotoxin Test|
|Sampled By||Chemical Analysis|
|Analysed By||Chemical Analysis|
|Done By (Sign & Date)|
|Checked By (Sign & Date)|
Mr. Shiv Kumar is the Author and founder of pharmaceutical guidance, he is a pharmaceutical Professional from India having more than 14 years of rich experience in pharmaceutical field.
During his career, he work in quality assurance department with multinational company’s i.e Zydus Cadila Ltd, Unichem Laboratories Ltd, Indoco remedies Ltd, Panacea Biotec Ltd, Nectar life Science Ltd. During his experience, he face may regulatory Audit i.e. USFDA, MHRA, ANVISA, MCC, TGA, EU –GMP, WHO –Geneva, ISO 9001-2008 and many ROW Regularities Audit i.e.Uganda,Kenya, Tanzania, Zimbabwe. He is currently leading a regulatory pharmaceutical company as a head Quality. You can join him by Email, Facebook, Google+, Twitter and YouTube