PERFORMANCE QUALIFICATION PROTOCOL OF WATER FOR INJECTION GENERATION AND DISTRIBUTION SYSTEM

WATER FOR INJECTION GENERATION AND DISTRIBUTION SYSTEM

Working Principle of Water For Injection System:

The Water For Injection System Still is working on the Principle of inters-stage heat exchange (Reuse of energy) to drastically reduce the consumption of heat energy and cooling water. Thus enables to production large- scale of Pyrogen free sterile water for injection. The Distillation Column operates at different pressures and temperatures making it possible to transfer the energy in the process forward column to column.

Brief Instrument Description:

Water for Injection System produces pyrogen-free, sterile water for injection which meets the requirements of international pharmacopeias including USP, BP, and IP. It operates on the distillation as a unit process. Sterile water generation engrosses with Liquid-vapor-liquid phase change to produce very high-purity water.

The water for Injection system works on the “Falling Film Evaporator” principle. It employs high temperature which assures constant sterile water.

The unit is designed to remove microbial contamination by three-stage separation. Several effects are connected in series. Each effect has an innermost evaporator (shell & tube heat exchanger), an intermediate separator, and an outer column. The source of energy for this effect is boiler steam & the remaining effects use the intrinsic heat to supplement the consumption needs of the heating energy.

Feed water is pre-heated by the waste heat recovery method and enters the first effect from the tube side. A specially designed distribution plate ensures the water falls down the tube as a “Thin film”. The falling film is heated with plant steam 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 change 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 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 blown 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 a lower temperature & pressure than the one preceding it. Pure steam condenses as WFI in each effect & 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.

The plant operates on a PLC system. PLC system ensures efficient working of the plant under favorable conditions. In case of violation of any critical condition, the plant will automatically stop & give an audio-visual signal to the operator. When the problem is solved, the plant will start automatically.

The system has the unique feature of purging which removes water containing pyrogen and other impurities and keeps the concentration of impurities to a minimum level.

So, WFI produced from each column except the first column will be collected at the bottom of the column & transferred to the cooler. Steam, which is produced in the final column, will also be taken to the cooler, which will convert into WFI.

Brief Description of Distribution System :

Control of the WFI distribution loop and WFI storage tank will be through a common PLC panel. Distribution of WFI through various user points provided in the loop system. WFI is generated using Multicolumn and stored in a WFI storage tank at 85°C to 90°C. It is pumped into a distribution loop using a centrifugal pump. One stand-by pump is also provided. All piping has Armaflex insulation with SS 304 cladding below the false ceiling and with aluminum foil above the false ceiling.

The return loop to the WFI tank has having following instrumentation and control.

Flow Indicator and Controller: – This will indicate the flow rate in the return line and will control the minimum return flow rate to the WFI tank using the VFD of the circulation pump.

Conductivity sensor and controller: The conductivity sensor will sense the conductivity of WFI coming in the return loop and if conductivity is beyond the set point, it will drain all WFI.

Temperature sensor, Transmitter, and Indicator: – It will sense the temperature of WFI in the return line and will indicate the same.

Performance Qualification Protocol Contents

  • Protocol Approval 
  • Overview
  • Objective: 
  • Purpose and Scope
  • Responsibility
  • Qualification Team
  • Training Record
  • Purpose/Scope
  • Performance Qualification Requirements
  • Performance Qualification Procedure
  • Re- Validation Critaria
  • Acceptance Criteria
  • Qualification Report
  • Observed Deviation
  • List of Exhibits/Annexures
  • List of Exhibits
  • List Annexure
  • Reference Documents  

Protocol Approval

This is a specific protocol for the Performance Qualification of Water for Injection generation, Storage, and Distribution Systems. This protocol has been approved

Final Approval:

Final approval has been given by the following: 

Objective:

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 the WFI generation, Storage, and Distribution system to:

  • Demonstrate that the WFI System shall perform reproducibly and consistently within 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.

Responsibility

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 collect 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 three phases of the validation study. The summary report of the Performance Qualification shall be prepared by the 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

Purpose

The purpose of the training is to familiarize the trainees with the principle of working & technical specifications of the WFI System as well as the overall strategy of Performance Qualification of the WFI Generation, Storage, and Distribution System.

Scope

This Training is related to the Water for Injection generation, storage, and distribution system and is being imparted to the people involved in the WFI water system validation.

Topics

The following topics to be covered during training:

Principle and operating of Water for Injection system.

Technical specifications of the system components.

The overall strategy of the Qualification process.

General precautions/guidelines to be followed during qualification.

Note: –

  • Training is given as per SOP Title: SOP on cGMP Training
  • Training records have been attached to the report

Performance Qualification Requirements

Following reagents/chemicals/standards shall be required for the Performance Qualification of Water for the Injection system

  • Bottles for Sampling.
  • All test solutions.
  • Media 

System/Equipment Details

  • Equipment Identification Number
  • Location
  • Name of the system/Instrument
  • Manufacturer’s Name
  • Model
  • Purchase Order Number
  • Date of Installation

Performance Qualification Procedure

The following procedure has been used for the performance qualification of Water for Injection generation, storage, and distribution system:

Water for the Injection System was checked for completion of the operational qualification activity.

The Performance Qualification of the 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 a rotation basis, for 8 months.

The phase-I study shall be done as per the 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 1 month)

The performance qualification of the Water for Injection System shall be started when all the equipment and piping of the WFI system have 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 1 month.

During this phase, water samples from all generation/usage points shall be analyzed and monitored for compliance with the pre-determined specifications.

After the successful completion of Phase-I of the performance qualification, the Water for Injection System should be cleared for the usage of WFI water in manufacturing operations. The 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 the 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 3 months)

Phase II of the performance qualification shall commence, after the successful completion of Phase I. The purpose of Phase II qualification is to monitor the operating parameters. The objective of Phase II is also to demonstrate that the system is producing the desired quality of water, consistently, when operated in conformance with the SOP established at the end of Phase I. Conclusions shall be mentioned in the Summary report.

During Phase II, WFI water samples shall be collected from various Sampling Points in the generation system as mentioned in the sampling plan and Usage Points daily. Phase II of the performance qualification of the Water for Injection System includes extensive sampling of WFI water from all sampling points in the Water for Injection System & usage points of the distribution loops daily. Phase II sampling was carried out for 3 months. Water samples from all the usage points shall be analyzed and monitored daily, for compliance with the pre-determined specifications.

After the 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 the 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 8 months)

  • Phase III of the performance qualification shall commence, after the successful completion of Phase II. The purpose of Phase-II qualification is to monitor the operating parameters. The objective of Phase III is also to demonstrate that the system is producing the desired quality of water, consistently, when operated in conformance with established SOP and does not have any seasonal variation through out the Phase III study to collect robust data. Conclusions shall be mentioned in the Summary report.
  • During Phase III, WFI water samples shall be collected from various Sampling Points in the Water for Injection System as mentioned in the sampling plan and Usage Points every week. Phase III of the performance qualification of the Water for Injection System includes extensive sampling of water from various points in the WFI water generation system & all the usage points of the distribution loops every week. Phase III sampling was carried out for 8 months. Water samples from all the usage points shall be analyzed and monitored weekly, for compliance to the pre-determined specifications.
  • Specifications of Water for Injection:
Test Parameter Specification
A. Chemical Analysis
Description Clear colorless, odorless, and tasteless liquid
pH (at 25°C) Between 5.0 to 8.0
Conductivity (at 25°C) NMT 1.3 µS / cm
Ammonium NMT 0.3 ppm
Calcium No turbidity observed
Chlorides NMT 0.50 ppm
Sulphates No turbidity observed
Total Organic Carbon NMT 500 ppb
Oxidizable Substance The solution remains faintly pink
Carbon Dioxide The solution should remain clear
B. Microbiological Analysis
Total Aerobic Microbial Count (TAMC) NMT 10 cfu / 100 ml
Bacterial Endotoxin Test NMT 0.125 EU / ml

 6.7      Sampling Plan & Frequency

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
WFI sampling points in the Generation system
After Column II As per WFI WFI – 01 NA Daily  

 

 

Daily

 

 

 

Weekly
After Column III As per WFI WFI – 02 NA Weekly
After Column IV As per WFI WFI  – 03 NA Weekly
After Column V As per WFI WFI – 04 NA Weekly
After WFI Generation As per WFI WFI – 05 NA Weekly
Storage Tank As per WFI WFI – 06 NA Daily
Usage points in the WFI Distribution loop system 
Garment Washing Room As per WFI WFI – 07  

Daily

 

 

 

 

 

Daily

 

 

 

 

 

Daily

Weekly
Equipment Washing and Sterilization Room As per WFI WFI – 08 Weekly
Vial Washing Room As per WFI WFI – 09 Weekly
Before Bung Processor As per WFI WFI – 10 Weekly
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 based on Phase-I and Phase-II data.

Alert levels are levels or ranges 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 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 the 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.

Acceptance Criteria

Performance qualification shall be considered acceptable when all the above requirements of this protocol have been fulfilled and all the parameters is functioning as per the design specifications and as per the manufacturer’s recommendations.

Qualification Report

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/annexures that were completed at the time of qualification activity.

Observed Deviation

Sr. No. Page No. Point No. Observed Deviation Deviation Reported By Deviation Approved By Corrective Action Taken Justification of Corrective Action

List of Exhibits / Annexures

List of Exhibits

Exhibit No. Exhibit Title No. of Pages
01 Datasheet for PQ test results of WFI Water
Total No. of pages

List of Annexures

Annexure No. Annexure Title No. of Pages
01 Training Record
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

Reference Documents

  • Design Qualification
  • Installation Qualification
  • Operation Qualification.
  • United States Pharmacopoeia.
  • Indian Pharmacopeia.

(Exhibit – E01 ) Data Sheet for PQ Test Results of WFI Water

System Name /Sampling Point No./Phase:  I/ II/ III

Date (è)
Test Parameters (ê) Results
Description  
pH (at 25°C)  
Conductivity (at 25°C)  
Ammonium  
Calcium  
Sulphate  
Total Organic Carbon  
Oxidizable Substance  
Carbon Dioxide  
Total Aerobic Microbial Count (TAMC)  
Bacterial Endotoxin Test  
Sampled By Chemical Analysis  
Microbiological

Analysis

 
Analysed By Chemical Analysis  
Microbiological

Analysis

 
Done By (Sign & Date)  
Checked By (Sign & Date)  

 Approved By/Date:

About Pharmaceutical Guidanace

Ms. Abha Maurya is the Author and founder of pharmaceutical guidance, he is a pharmaceutical Professional from India having more than 18 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

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