Performance Qualification Protocol

Pure Steam Performance Qualification , Purpose

Pure Steam Performance Qualification , To determine that the Pure steam generator performs as per the given specifications, by running the system on its intended schedules and recording all relevant data under normal conditions & for worst-case situations where applicable.

Pure Steam Performance Qualification , Scope

This Performance Qualification (PQ) is to be performed against agreed acceptance criteria on the pure steam generator system Cephalosporin Block of XX Pharmaceuticals Ltd. The scope will include the measurement of Non-condensable gases, superheat value, dryness value and microbiological test of pure steam system.

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Responsibilities

[][]Preparation of the protocol
=>Validation (Engineering) Department with the assistance of Microbiology, Quality Assurance and Engineering department.

[][]Executing the protocol
=>Validation team along with respective departmental person and engineers or other suitably qualified staffs allocated from the site or contracted specialists as appropriate.

[][]Non-condensable gas, superheat value, dryness fraction
=>Validation (Engineering) Department

[][]Microbiological Test
=>Microbiology Department

[][]Data documentation and preparation of the report
=>Validation (Engineering) department.

[][]Verifying of the report
=>Concerned departmental person.

[][]Providing documentation on the equipment
=>Related departments i.e. Engineering, Production, Microbiology, Validation or other appropriate departments and manufacturer.

System And Process Description

=>System Information
=>Manufacturer : Watertown
=>Capacity : 200kg/hr
=>Model : MS750/4T
=>Serial No. : MS1132

Reference Instruments

=>Name : Steam quality test kit
=>Manufacturer : Dekon Solutions, UK
=>Model : SQ kit Option – A.

The System under test

[][]The pure steam is generated in the WFI plant located at the roof top utility area of Cephalosporin Block. Industrial steam enters into the first heat exchanger of WFI plant and exchanges heat with the purified water and is converted into pure steam. Therefore, pure steam is supplied at a pressure of around 2.5 bar – 4 bar to the autoclave room of sterile area of cephalosporin block.

Performance Tests

[][]The tests for performance qualification of pure steam as follows:

=>Non-condensable gas test
=>Test Method

[][]The measurement of non-condensable gases is made by cooling a steam sample, using water through an efficient condenser.
[][]Water can be supplied either directly from a pressurized supply or simply by siphoning from a tank at a flow rate of 200ml/minute, provided that a minimum head of 1.0 meter is maintained and at a temperature not exceeding 250C.
[][]When the sampled steam is condensed, any non-condensable gases that may be present are liberated and separated from the produced condensate into two sight glass columns.
[][]The gas and steam condensate volumes are measured by the ‘zero adjustable’ scale mounted behind the two sight glasses.
[][]Perform the test for 3 consecutive working days.
[][]Record the result in Appendix 1.

 Acceptance Criteria

[][]The results of the non-condensable gas test are deemed to be acceptable for sterilization purposes if the percentage of gas to condensate is less than 3.5%.
[][]Observations:
[][]Done by: Checked by:

Steam Superheat Value

Test Method
[][]The temperature of steam passing through an orifice in a pitot tube is measured.
[][]The temperature is measured by using a thermocouple which is located at the centre of the expansion tube placed over the pitot tube.
[][]The test is intended to demonstrate that the amount of moisture in the steam supply is sufficient to prevent the steam from being superheated as it enters the expanded space of a sterilizer chamber.
[][]Perform the test for 3 consecutive working days.
[][]Record the result in Appendix 2.

Acceptance Criteria

The temperature of the pure steam is considered to be acceptable if it is less than 250C above that of the local temperature of boiling water, which is altitude dependent.

Pure Steam Dryness Value

Test Method

[][]The purpose of the steam dryness value test is to ensure that an acceptable amount of moisture is present in the steam supply. If too little moisture were present, superheating of the steam may occur.

[][]Too little moisture may also prevent the optimum sterilization conditions occurring within the sterilizer load because, moisture is the critical factor breaking down the cell structure of sporing organisms.

[][]The method employed is the heat balance using a stainless steel vacuum flask. The principal being that the flask is primed with a known mass of water at a known temperature.

[][]Steam is then condensed in the flask thus raising the temperature of the water. When the final mass and temperature of the water are measured and placed to the excel worksheet, provided by the manufacturer of the Steam Quality Test Kit, the dryness value is calculated.
[][]Perform the test for 3 consecutive working days.
[][]Record the results in Appendix 03.

Acceptance Criteria

=>The Pure Steam Dryness Value must be within 0.9 – 0.95.

Chemical tests

Test Method

[][]Three tests will be performed as chemical tests such as Appearance test, conductivity as well as TOC. The pure steam will be collected in a depyrogenated flask and the chemical tests would be performed for the condensate of the pure steam. Wear hand gloves and goggles while collecting the sample.
[][]Perform the test for 3 consecutive working days.
[][]The results will be provided from the Quality Control department in the respective forms and will be attached with the report.

Acceptance Criteria:

=>The specifications of these tests according to QC/SPEC/RMEXXX/01:

Tests	Acceptance Limit
Appearance	Clear, colorless and odorless liquid.
Conductivity	Not more than 1.1µS.cm-1 at 200C Or Not more than 1.3µS.cm-1 at 250C
TOC	Not more than 0.5 mg/L

Microbiological tests

Test Method

[][]Microbiological tests will be performed by collecting the pure steam in a depyrogenated flask. Wear hand gloves and goggles while collecting the sample.
Perform the test for 3 consecutive working days.
[][]The results will be provided from the Microbiology department in the respective forms and will be attached with the report.

Acceptance Criteria:

The specifications of these tests according to QC/SPEC/RMXXX/01:

Tests	Acceptance Limit
Total viable Microbial Count	Not more than 10 CFU/100mL.
E.Coli	Must be absent
Staphylococcus aureus	Must be absent
Pseudomonas aeruginosa	Must be absent
Salmonella spp	Must be absent
Bacterial Endotoxins	Less than 0.25 EU/ml

Sampling Points and Test Frequency

The list of sampling points which come into product contact is given below:

Sl. No.	Sampling point name	Room No.	Block	Room Name	Tests	Frequency
01	PS – 01	SPR0XX	Cephalosporin	Autoclave	Non-condensable gas, steam superheat value, steam dryness factor, chemical and microbiological tests.	6 months.

Deviation And Failure Investigation Summary

[][]In the column below, record any deviation or failure that occurred during the PQ exercise.

Report Summary

The report summary of performance qualification of Pure Steam system shall be mention here.

Conclusion

The Performance Qualification of the Pure Steam system of Cephalosporin Block Complies / Does Not Comply with the acceptance criteria taken above and the results obtained are attached with the protocol.
The Pure Steam system is / is not qualifying the Performance Qualification test as per this Protocol. Hence, the system can be / cannot be used for production operation.

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Performance Qualification of Pure Steam Protocol

Vial Filling Machine Performance Qualification, Purpose

[][] Vial Filling Machine Performance Qualification, The purpose of this protocol is to provide an outline for the Performance Qualification of Vial/Vial Filling Machine to:
=>Demonstrate that the system performs as intended by repeatedly running the system on its intended schedules under normal operating conditions and worst-case conditions, where appropriate.
=>To assess the machine capability to fill consistent volumes at various running speed.
=>To check the stoppering of vials.
=>To check the presence of any particulate matter visually.

Vial Filling Machine Performance Qualification, Scope

[][]The aim of this qualification is to perform the performance qualification of the following machine. It is documented evidence that the machine installed properly and functions correctly in accordance with the desired specification as well as manufacturer’s information. It also certifies that the machine operates reliably and within prescribed or specified operating limit. This protocol covers the following machine:

=>Equipment Name

=>Machine No.

=>Location

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Responsibility

[][]Protocol preparation as per the guideline of Validation Master Plan
=>Validation Dept.
[][]Check & review of the protocol
=>Validation & Technical Expert*
[][]Approval of protocol prior to execution
=>Head of Validation, QA, Engg., Plant
[][]M/C operation , testing and data processing
=>Validation team
[][]Microbiology challenge test
=>Microbiology
[][]Preparation of report
=>Validation Dept.
[][]Check & review of the report
=>Validation & Technical Expert*
[][]Approval of the qualification report
=>Head of Validation/QA/Engg./Plant
[][]Authorization of the report
=>Director, Technical Operations
[][]Protocol preparation as per the guideline of Validation Master Plan
=>Validation Dept.

System and process Description

The Vial filling and stoppering machine is used to fill and stopper the vials. The machine consists of following parts:

Line 1:
[][]This line is a compact filling line with capacity to fill around 6000 Vials/ hr. This machine can fill from 0.3 ml to 2.1 ml. In brief its function is as follows:
[][]The vials are fed upright from a depyrogenation tunnel connected to upstream on to an in feed rotary table.
[][]This table rotates continuously and guides the vials with various deflectors through two infeed lanes into the walking beam transport system.
[][]There are two sensors attached in each lane to detect fallen containers, which after detection goes to bin.
[][]These containers are stopped by two infeed gates.
[][]If there are enough containers in the in feed tracks the container feed sensors at the in feed are actuated and infeed gates open.
[][]The walking beam advances the containers intermittently to various work station where two containers are processed at each machine cycle as per following sequence:

Nitrogen flushing=>Filling=>Nitrogen flushing =>Stoppering=>Discharge=>stopper Checking =>Visual Inspection=>Confirmation

Machine consists of following parts:.

Infeed Rotary Table —

[][]The containers are placed upright on the infeed rotary table by the machine upstream- The containers are conveyed continuously until they are stopped by infeed gates.
[][]There is ultrasonic sensor on table which detects Quantity of containers on the table.
[][]If too many containers accumulate on table then sensor give message to tunnel to reduce the speed of tunnel automatically.
[][]When Quantity is reduced , automatically tunnel increase its speed.

Container feed tracks and monitoring –

[][]The containers from above table are feed into two tracks, where they pass an outlet in the rim of table where fallen containers roll out into a bin beneath the rotary table.
[][]A sensor is located in each feed track. If the container supply in one of the track is very much low , then infeed gates closes, so no further container enter the machine from this track.
[][]When the supply replenish the gates reopen.

Infeed gates

[][]The containers arriving in the infeed tracks are stopped by the infeed gates and are prevented from entering the walking beam.
[][]When the infeed gates are switched on at the operating panel, each gate opens to let containers into transport system provided that the respective container feed sensor detect sufficient containers in the track.

Container Registration sensor

[][]This detect the containers in walking beam and transform information to machine cycle to start the process.
[][]If no container is detected then work station is blocked automatically.

Walking beam transport System –

[][]This system transport the vials through the machine.
[][]They are conveyed upright on a base guide between walking beam and the counterguide.
[][]This walking beam consist of two parts : one part centers the vials and the other one transport them.

Liquid dosing unit –

[][]The product is filled by 2(two) rotary piston pump. The amount dispensed is virtually proportional to the pump stroke.

[][]As the pump piston rise. Product is drawn from the manifold to the pump via hoses.

[][]The piston then turns through 180°, so that the grooves are directed towards the filling needle.
[][]As the pistons are lowered, the product is discharged through dosing hoses and filling needle in to the vials.
[][]This dose can be adjusted by altering the pump stroke.

Gas-flushing Equipment –

[][]Two needles for pre flushing and two needle for post flushing are provided in this system.
[][]The gas flushing needles are lowered in containers with the filling needle movement and flush the container interior with 0.2µ filtered Nitrogen, thereby displacing the ambient air from the container.

Stopper insertion station –

[][]At this station the rubber stoppers are placed on the neck of containers and then pressed in.
[][]The vacuum required for the insertion station is provided by inbuilt vacuum pump.
[][]This station consists of Stopper feed, sorting bowl filling level monitor, Feed track monitoring, stopper check sensors, discharge wheel and tray loading unit.

Line-2:

[][]This line is a compact filling line with capacity to fill around 12000 ampoules/ hr. It has ampoule sealing machine also. This machine can fill from 0.3 ml to 2.1ml. In brief its function is as follows:
[][]The Ampoules are fed upright from a Depyrogenation tunnel connected to upstream on to a in feed belt.
[][]At the end of belt the ampoules are picked by the feed scroll, spaced by the recesses of the scroll and pushed into the individual transport recesses around the periphery of star wheel.
[][]The star wheel conveys the ampoules in a continuous movement and present to individual work stations.
[][]The rotation discs located at the work stations rotate the ampoules during all the work process to ensure smooth functioning of each step.
[][]All the work stations move forward synchronously with the containers during ampoule processing and swivel back to initial position after end of process.
[][]Four ampoules are processed at each machine cycle with following sequence:

Nitrogen flushing=> Filling =>Nitrogen flushing =>Heating of tips of Ampoules =>Sealing by Fusing =>Pulling of Ampoule tips=>Discharge

Machine consist of following parts:.

Infeed belt

[][]The containers are placed upright on the infeed belt by the machine upstream.
[][]If too many containers accumulate on belt then sensor give message to tunnel to reduce the speed of tunnel automatically.
[][]When Quantity is reduced, automatically tunnel increase its speed.
[][]If no container arrive from tunnel, then infeed scroll of AFV stops, preventing any further ampoules from entering the star wheel.

Container Registration sensor

[][]Before each transport recess on the star wheel reaches the first work station, a light sensor checks for the presence of Ampoule.
[][]If ampoule is detected, the pulse emitted by the photoelectric sensor is memorized in electronic control and this information is transferred for running all machine cycles.
[][]If no ampoule is detected then work stations are blocked automatically..

Liquid dosing unit

[][]The product is filled by 4(Four) rotary piston pump. The amount dispensed is virtually proportional to the pump stroke. As the pump piston rise.
[][]Product is drawn from the manifold to the pump via hoses.
[][]The piston then turns through 180°, so that the grooves are directed towards the filling needle.
[][]As the pistons are lowered, the product is discharged through dosing hoses and filling needles in the ampoules.
[][]This dose can be adjusted by altering the pump stroke.

Gas-flushing Equipment

[][]Four needles for pre flushing and Four needle for post flushing are provided in this system.
[][]The gas flushing needles are lowered in Ampoules with the filling needle movement and flush inside the Ampoule interior with 0.2µ filtered Nitrogen, thereby displacing the ambient air from the Ampoule.

Line 3 :

[][]This line is a compact filling line with capacity to fill around 6000 vials/ hr.
[][]It is also set for full stoppering as this line is only for liquid filling.
[][]This machine can fill from 0.3 ml to 2.1 ml. This machine is same as line 1.

Line 4:

[][]This line is a standalone filling line with capacity to fill around 6000 vials/ hr.
[][]It is also set for full stoppering as this line is for liquid filling.
[][]This machine can fill from 0.7 ml to 5.5 ml and 8 ml to 50 ml.
[][]In this machine the vials are sterilized in Dry Heat sterilizer in trays and are feed manually to machine.

Tests To Be Performed and Planned

Sl.No	Test	Plan/Frequency
01	Consistency in fill volume at various speed	Consecutive 3 runs
02	Proper Stoppering	Consecutive 3 runs
03	Check of presence of any particulate matter	Consecutive 3 runs

Test Details and Records

Consistency of Filled Volume

[][]The vial filling machine is started at a main drive motor speed of 100% and after 15 minutes 10 vials are collected to check the consistency of filled volume.
The same procedure is repeated for 90% and 80% main drive motor speed.
[][]Result is recorded in the result sheet form.

Record of consistency of filled volume

=>Media used for filling
=>Vial Size

Particulars	Run 1 Date:	Run 2 Date:	Run 3 Date:
No. of 3ml vials to fill at main drive motor speed of 100%
Average volume of 10 Vials at 15 Minutes after start
No. of 3ml vials to fill at main drive motor speed of 90%
Average volume of 10 Vials at 15 Minutes after start
No. of 3ml vials to fill at main drive motor speed of 80%
Average volume of 10 Vials at 15 Minutes after start

Acceptance Criteria:  The filled volume has to be within 10ml ± 0.5ml.

Check of Stoppering

[][]In each run 20 vials are collected to visually check the stoppering.

Result of checking stoppering

Run no.	Date	No. of properly stroppered vials	No. of not properly stroppered vials	Percentage of rejected vials

Acceptance Criteria:   The number of rejected vials has to be less than 1.0%.

Check of presence of any particulate matter

[][]In each run 20 vials are collected to check the presence of any visible particulate matter.

Result of checking presence of any particulate matter

Run no.	Date	No. of total filled vials	No. of rejected vials	Percentage of rejected vials

[][]Acceptance Criteria:   The number of rejected vials has to be less than 1.0%.

Report Summary

[][]The Performance Qualification study for Vial/Vial Filling machine was carried out for 3 consecutive date and following result summary was obtained.

No.	Tests	Acceptance limits	Run 1 Passed (Y/N)	Run 2 Passed (Y/N)	Run 3 Passed (Y/N)
01	Consistency in fill volume at various speed	NMT 0.5ml Variation from adjusted Limit
02	Proper Stoppering	99% Complies
03	Check of presence of any particulate matter.	99% Complies

The Result of this Performance Qualification study was recorded, summarized and analyzed. The observed parameters/tests and subsequent analytical results show that the vial filling machine perform as per predetermined acceptance criteria. Hence, the machine successfully qualifies the performance Qualification test.

Conclusion

The performance qualification complies with the acceptance criteria taken above and the results obtained are attached to the protocol.

Vial/Vial Filling Machine bearing Equipment ID No. ……….………….Is / Is Not qualifying the Performance Qualification test as per the guideline described in this Protocol No. ————- and Can Be / Cannot Be use for production.

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Vial Filling Machine Performance Qualification Protocol

Cartridge Filling Machine Performance Qualification, Purpose

[][]Cartridge Filling Machine Performance Qualification, The purpose of this protocol is to provide an outline for the Performance Qualification of Vial/Cartridge Filling Machine to:
[][]Demonstrate that the system performs as intended by repeatedly running the system on its intended schedules under normal operating conditions and worst-case conditions, where appropriate.
[][]To assess the machine capability to fill consistent volumes at maximum and minimum running speed.
[][]To verify the gliding force of filled cartridges.
[][]To ensure proper stoppering.
[][]To check the air bubble size with respect to glass bead size.

Cartridge Filling Machine Performance Qualification, Scope

[][]The aim of this qualification is to perform the performance qualification of the following machine. It is documented evidence that the machine installed properly and functions correctly in accordance with the desired specification as well as manufacturer’s information.
[][]It also certifies that the machine operates reliably and within prescribed or specified operating limit. This protocol covers the following machine:

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Vial Filling Machine Performance Qualification Protocol

Responsibility

[][]Validation Dept.
Protocol preparation as per the guideline of Validation Master Plan
[][]Validation & Technical Expert*
Check & review of the protocol
[][]Head of Validation, QA, Engg., Plant
Approval of protocol prior to execution
[][]Validation team
M/C operation , testing and data processing
[][]Microbiology
Microbiology challenge test
[][]Validation Dept.
Preparation of report
[][]Validation & Technical Expert*
Check & review of the report
[][]Head of Validation/QA/Engg./Plant
Approval of the qualification report
[][]Director, Technical Operations
Authorization of the report
[][]Validation Dept.
Protocol preparation as per the guideline of Validation Master Plan

System and process Description

[][]The Cartridge filling and stoppering machine is used to fill and stopper the Cartridges. The machine consists of following parts:
[][]This line is a compact filling line with capacity to fill around 2500 cartridges/ hr. The cartridges are fed upright from a depyrogenation tunnel connected to upstream on to an in feed rotary table.
[][]There is a vibrator by which this table is vibrated continuously and guides the cartridges with various deflectors through infeed lanes into the filling portion. There is a sensor to detect fallen containers.
[][] If there is any fallen cartridge, it shows alarms on the display and the machine is stopped. If there are enough containers in the in feed tracks the container feed sensors at the in feed are actuated and infeed gates open. After coming through the in feed rotary screw the glass beads are inserted into the cartridges.
[][]There are two rotary piston pumps for transferring the filling media from vessel to the two filling nozzles. First nozzle is for filling half of the required volume and second one is for remaining half.
[][] There is a nozzle for sucking the access media at the 2nd filling nozzle. The filling volume is virtually proportional to the stroke of the piston pumps.
After filling, the flip off seals are attached at the top of the cartridges.
[][]There is a container for flip off seals and these are transferred by using the vibration. A proximity sensor detects the presence of flip off seals.
[][]The whole process occurs under a Laminar Air Flow Unit which ensures a clean area of Class A (ISO Class 5). The flow diagram of filling machine is as follows:

Tests To Be Performed and Planned

SR./NO.	Test	Plan/Frequency
01	Consistency in fill volume at various speed	Consecutive 3 runs
02	Gliding force measurement for filled cartridges.	Consecutive 3 runs
03	To check the bubble size with respect to size of Glass beads.	Consecutive 3 runs
04	To check proper stoppering.	Consecutive 3 runs

Test Details and Records

Consistency of Filled Volume

[][]The cartridge filling machine is started at a main drive motor speed of 100% and after 15 minutes 10 cartridges are collected to check the consistency of filled volume.
[][]The same procedure is repeated for 90% and 80% main drive motor speed.
[][]Result is recorded in the result sheet form.

Record of consistency of filled volume

Cartridge Size	Run 1 Date:	Run 2 Date:	Run 3 Date:
No. of 3ml cartridges to fill at main drive motor speed of 100%
Average volume of 10 Cartridges at 15 Minutes after start
No. of 3ml cartridges to fill at main drive motor speed of 90%
Average volume of 10 Cartridges at 15 Minutes after start
No. of 3ml cartridges to fill at main drive motor speed of 80%
Average volume of 10 Cartridges at 15 Minutes after start

Acceptance Criteria: The filled volume has to be within 3ml ± 0.3ml.

Gliding Force for Filled Cartridges

[][]10 cartridges are marked and loaded with the cartridges of total batch.
[][]After filling and stoppering 10 filled cartridges are collected at 15 minutes after starting the machine at a speed of 100% of main motor.
[][]The procedure is repeated twice by varying the speed to 90% and 80% of the main motor.

Record of Gliding Force for Filled Cartridges

Run no.	Gliding Force Measuring Machine Specification	Date	Average Gliding Force (Newton)	Met Acceptance Criteria (Y/N)
01
02
03

Acceptance Criteria: The gliding force has to be less than 20N.

Bubble Size

[][]In each run 20 cartridges are collected to visually check the presence of glass beads and the bubble size with respect to glass bead size.

[][]Result of checking bubble size

Run no.	Date	Glass bead present (Y/N)	Bubble present (Y/N)	Bubble size is smaller than glass bead size (Y/N)	Percentage of rejected cartridges

Check of Stoppering

In each run 20 cartridges are collected to visually check the stoppering.

Result of checking stoppering

Run no.	Date	No. of properly stroppered cartridges	No. of not properly stroppered cartridges	Percentage of rejected cartridges

Acceptance Criteria: The number of rejected cartridges has to be less than 10%.

[][]List of Reference Involved in Validation Study

[][]Details Of Attachments To Validation Report

Report Summary

The Performance Qualification study for Vial/Cartridge Filling machine was carried out for 3 consecutive date and following result summary was obtained.

No.	Tests	Acceptance limits	Run 1 Passed (Y/N)	Run 2 Passed (Y/N)	Run 3 Passed (Y/N)
	Consistency in fill volume at various speed	NMT 0.3ml Variation from adjusted Limit
	Gliding force for filled cartridges	Gliding Force for filled cartridges has to be less than 20 Newton.
	Bubble Size	Bubble size has to be less than glass beads size.
	Proper Stoppering	99% Complies

[][]The Result of this Performance Qualification study was recorded, summarized and analyzed. The observed parameters/tests and subsequent analytical results show that the cartridge filling machine perform as per predetermined acceptance criteria. Hence, the machine successfully qualifies the performance Qualification test.

Conclusion

[][]The performance qualification complies with the acceptance criteria taken above and the results obtained are attached to the protocol.

[][]Vial/Cartridge Filling Machine bearing Equipment ID No. ……….………….Is / Is Not qualifying the Performance Qualification test as per the guideline described in this Protocol No. ————- and Can Be / Cannot Be use for production.

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Performance Qualification of Cartridge Filling Machine Protocol

Depyrogenation Tunnel Performance Qualification, Purpose

Depyrogenation Tunnel Performance Qualification, To authenticate and document that the performance of the Depyrogenation Tunnel of Sterile Production area (Cephalosporin Block) of XX Pharmaceutical Limited (PPL) is satisfactory in all critical aspects related to the operational requirements. This protocol describes the performance qualification procedures of the Depyrogenation Tunnel manufactured by Tofflon, China.

Depyrogenation Tunnel Performance Qualification, Scope

This Performance Qualification (PQ) is to be performed against agreed acceptance criteria on the vials of three sizes such as 7.5 ml, 15 ml and 30 ml, which will be sterilized by the Depyrogenation Tunnel installed in the Sterile Production area of Cephalosporin Block of XX Pharmaceutical Limited.

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Responsibilities

Preparation of the protocol

[][]Validation (Engineering) Department with the assistance of Microbiology, Engineering and Maintenance department.

Executing the protocol

[][]Validation (Engineering) Department along with respective departmental person and engineers or other suitably qualified staff allocated from the site or contracted specialists as appropriate.

Microbiological Challenge Test

[][]Microbiology department

Data documentation and preparation of the report

[][]Validation (Engineering) department.

Verifying of the report

[][]Concerned departmental person.

Providing documentation on the equipment

[][]Related departments i.e. Engineering, Production, Microbiology, Validation or other appropriate departments and manufacturer.

Equipment Information

=>Manufacturer : Tofflon, China
=>Capacity : 6000-9000 vials /hr
=>Model : SZA 620
=>Serial no. : YF2014-078B

The Equipment under test

[][]The Depyrogenation tunnel under validation study has the following segments:
=>Pre-heating zone
=>Sterilization zone
=>Cooling zone
[][]The whole production process combines in a line consecutively with a Vial washing machine, Depyrogenation tunnel, Vial Filling machine and Cap sealing machine.

[][]The washed Vials are conveyed into the Pre-heating Zone of the Depyrogenation tunnel automatically after washing in the vial washing machine.

[][]The Vials are flooded with sterile air in this zone. The temperature controlling preset values maintain the circulating air temperature at that preset value.

[][]The warm Vials are then transported into the Sterilizing Zone and are sterilized & depyrogenated by a low turbulence air flow (up to 300°C). The air is heated in an air circulation duct and then flows through the high temperature HEPA filters prior to reaching the vials.

[][]These filters ensure that the air quality corresponds to clean room class A (class 5 according to ISO 14644) in all operation modes, even in the heating and cooling phases. In the last work zone (cooling zone) of the tunnel, the sterilized Vials are cooled down by a vertical low turbulence air flow.

[][]The discharge from the tunnel opens into a clean room where the depyrogenated Vials are stored on a turn table and conveyed by belt transfer system to the infeed of filling machine.

Checking Parameters

[][]The PQ of Depyrogenation Tunnel will be carried out to evaluate the following conditions to confirm the sterilization conditions:
=>Heat Penetration (HP) studies.
=>Microbiological Challenge (MC) test using Endotoxin Challenge Vials.

The system/ equipment to be used as Standard for testing

[][]Performance of the Depyrogenation Tunnel will be judged based on thermal and biological studies which are mentioned below:
=>Equipment Name: Anville Data Logger, TQ Soft Version 6.1.2 with thermocouples.
=>Requirement for challenge test: -Endotoxin Challenge Vials.

Pre requirement For Validation:

[][]Calibration of thermocouples of the data logger/Validator before and after validation with proper identification.
[][]Valid calibration record of Data Logger/Validator.
[][]Data logger reading intervals set at 30 seconds (maximum).
[][]Successful calibration of the Temperature sensors of Depyrogenation Tunnel.
[][]Successful completion of IQ and OQ.
[][]Endotoxin Challenge Vials for ensuring 3 log reduction.

Study Procedure:

Heat Penetration (HP) Study:

[][]The equipment must be run three times at fully loaded condition for each size of vial where seven thermocouples are exposed to monitor the temperature within the loads.
[][]The number of measurement points will be dependent of the width of the tunnel. As the width of the tunnel is 590 mm, seven thermocouples will be placed at 98 mm distance from each other as shown in Appendix – 01.
[][]The conveyer belt of the tunnel will be run at about 98.4 mm/min and 90.2 mm/min for 7.5ml, 15ml and 30 ml vials respectively.
[][]Care must be taken to avoid contact between the thermocouples and the metal surface of the chamber. Evenly distribute the thermocouples as it is shown in the Appendix – 01.
[][]The Results of this test will be recorded in the Appendix-03 (Number of this appendix will be increased as per number of cycles) and will be accepted if met the acceptance criteria.

Microbiological Challenge (MC) test:

[][]This test will be performed while performing the HP study. Seven Endotoxin challenge Vials (ECV) are distributed along with the thermocouples at defined positions of conveyer belt of tunnel at fully loaded condition as per specified load pattern as specified in Appendix -1.
[][]After completion of the cycle ECVs will be tested by the microbiology department for required log reduction.
[][]The results of above test should be recorded in the designated form (Appendix-4).

Acceptance Criteria

For Heat Penetration (HP) study:

[][]During sterilization period; all thermocouple readings must be within set temperature (300deg.C)±15deg.C.
[][]During sterilization period; when all thermocouples are showing a minimum of 285deg.C, temperature difference among the thermocouples are not more than 15deg.C.
[][]For cooling zone performance study:
[][]After passing sterilization zone, minimum reading of all thermocouples are below 35deg.C.

For Microbiological Challenge Test:

[][]The ECVs not exposed to the Depyrogenation cycle (control) should show clot after incubation at time and temperature as per COA.
[][]The Endotoxin content of a challenge vial must be reduced at least 1000 fold (> 3 log reduction).

Deviation And Failure Investigation Summary

In the column below, record any deviations or failures that occurred during the PQ exercise.

Deviation/ Failure No.	Description and Assessment of Impact on Validation	Initial	Date
1
2
3

Reference Documents

[][]FDA Guidance for Industry ( for the Submission Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products).

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Depyrogenation Tunnel Performance Qualification Protocol

Autoclave Performance Qualification Protocol, Purpose

Autoclave Performance Qualification Protocol, To authenticate and document that the performance of the Autoclave (Steam sterilizer) of Sterile Production area (Cephalosporin Block) of XX Pharmaceutical Limited (LPL) is satisfactory in all critical aspects related to the operational requirements during sterilization of porous, solid and liquid loads. This protocol describes the performance qualification procedures of the Autoclave manufactured by Zirbus, Germany.

Autoclave Performance Qualification Protocol, Scope

This Performance Qualification (PQ) is to be performed against agreed acceptance criteria on different types of loads which will be sterilized by the Autoclave (Steam Sterilizer) installed in the Sterile Production area of Cephalosporin Block of XX Pharmaceutical Limited.

[][]Preparation of the Protocol
Validation (Engineering) Department with the assistance of Microbiology, Engineering and Maintenance department.
[][]Executing the protocol
Validation (Engineering) Department along with respective departmental person and engineers or other suitably qualified staff allocated from the site or contracted specialists as appropriate.
[][]Microbiological Challenge Test
Microbiology department
[][]Data documentation and preparation of the report
Validation (Engineering) department.
[][]Verifying of the report
Concerned departmental person.
[][]Providing documentation on the equipment
Related departments i.e. Engineering, Production, Microbiology, Validation or other appropriate departments and manufacturer.

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Depyrogenation Tunnel Performance Qualification Protocol

System and process Description

Equipment Information

=>Manufacturer : ZIRBUS, Germany
=>Capacity : 702 Ltr.
=>Model : HST 6×6×12
=>Serial no. : 3609

The Equipment under test

[][]The autoclave under validation study is a double door horizontal autoclave; chamber is made of SS 316L. The product is fed into the chamber via a loading port and drawn off after the sterilization cycle via the discharging port in a clean room of Grade B.
[][]A chamber leak test is performed to ensure that there is no leakage. It is very important to remove the air from the chamber. A water ring vacuum pump is used to remove the air from the chamber.
[][]For porous loads pre vacuum is important to remove the air pockets from the pores of the loads. To remove residual air vacuum pulse followed by steam pulse is used. After completion of vacuum and steam pulse the chamber is heated up with pure steam to the set sterilization temperature.
[][]There are two temperature sensors of which one is set inside the chamber and another is set in the drain port of the chamber. When the solid cycle is run, the drain temperature sensor controls the cycle. On the other hand, when the liquid cycle is run, the product temperature sensor controls the cycle

Checking Parameters

The PQ of autoclave will be carried out to evaluate the following conditions to confirm the sterilization conditions:
=>Chamber Leak Test (LT).
=>Bowie-Dick (BD) test.
=>Heat Penetration (HP) studies.
=>Microbiological Challenge (MC) test using Biological Indicators (BI).

The system/ equipment to be used as Standard for testing

Performance of the autoclave will be judged based on thermal and biological studies which are mentioned below:
=>Equipment Name: Anville Data Logger, Series 825 NATO.
=>Software: TQ Soft version 6.0

Requirement for challenge test:

=>Bowie-Dick test pack
=>Biological Indicator
[][]After completion of the cycles, all individual cycle records are summarized and compared with the autoclave printouts to verify the cycle consistency and performance.
[][]For Biological studies, Biological Indicators will be placed along with probes and will be studied for microbiological challenge test.

Pre requirement For Validation:

[][]Calibration of thermocouples of the data logger/Validator before and after validation with proper identification.
[][]Valid calibration record of Data Logger/Validator.
[][]Data logger reading intervals set at 30 seconds (maximum).
[][]Successful calibration of the Pressure and Temperature sensors of autoclave.
[][]Successful completion of IQ and OQ of Autoclave.
[][]Tubes of Geobacillus Stearothermophilus spores will be used as biological indicators. They should be labeled and placed at the front, middle and back of the autoclave chamber.

Study Procedure:

Chamber Leak (CL) Test:

[][]Thermocouples and reference pressure transducer are introduced into the chamber via the validation port. Then, the port and doors are sealed properly. There is a cycle, named as “Vacuum air test” cycle for leak test which is programmed in the PLC of the machine.
[][]During leak test, chamber pressure is reduced to a 70 mbar pressure and then this pressure is compensated and hold for 5 and 10 minutes respectively. The test is declared passed if the pressure rise is within 13 mbar within the holding time.
[][]If there is any leakage of steam for disintegration of gasket or any other reason, the autoclave might fail to achieve vacuum and leak test will be failed.
The results of above test will be recorded in the Appendix – 03 and will be accepted if met the acceptance criteria.

Bowie-Dick (BD) test:

[][]The Bowie-Dick (BD) test is done to detect air pockets and to evaluate that the vacuum retains as well as steam penetrates sufficiently for sterilization. This is because, air removal from the pores of the loads is essential for proper sterilization and to remove this air pre-vacuum pulse is important.
[][]For conducting this test, Bowie-Dick test paper kits will be exposed for 10 minutes at a temperature of 121.1OC inside the chamber. If the color of the centered sheet turns completely into black, it ensures proper vacuum of the chamber as well as proper steam penetration into the load and the test will pass.
[][]Any intermediate color change of centered sheets except black (e. g. grey, brown or blue) indicates the presence of residual air in the chamber.
[][]So, the test will fail. It may occur due to the failure of retaining required vacuum of the chamber and the insufficient steam penetration.
[][] In that case, increase the pre-vacuum pulse number or sterilization time which will ensure proper removal of air as well as the steam penetration respectively. This must be recorded in the report.
[][]The successful bowie-dick test’s pre-vacuum pulse numbers and sterilization time must be followed in the porous loads’ cycle.
The results of above test should be recorded in the Appendix – 04 and will be accepted if met the acceptance criteria.

Heat Penetration (HP) Study:

[][]The equipment must be run three times at fully loaded condition for each load pattern where twelve sensors are exposed to monitor the temperature within the loads as well as in the chamber.
[][]Care must be taken to avoid contact between the thermocouples and the metal surface of the chamber.
[][]Evenly distribute the thermocouples as it is shown in the Appendix – 2. In case of liquid load place the thermocouple no. 02, 03, 07 inside the container of the liquid.
[][]The Results of this test will be recorded in the Appendix-05 (Number of this appendix will be increased as per number of cycles) and will be accepted if met the acceptance criteria.

Microbiological Challenge (MC) test:

[][]This test will be performed with HP study. The temperature probes are distributed at different positions within the chamber and loads as per specified load pattern. Biological Indicators are placed beside the thermocouples as per BI placement diagram (Appendix – 01).
[][]It is to be noted that the Microbiological challenge test will be conducted for the heat penetration study cycles. Furthermore, the lethality value (F0) must be calculated by the TQ software and minimum lethality value must be recorded in Appendix 06.
[][]The results of above test should be recorded in the designated form (Appendix – 06). (Number of this Appendix will be increased as per number of cycles).

Acceptance Criteria

Chamber Leak test:

=>This test is deemed to be passed if the pressure rise of the chamber is within 13 mbar.

For Bowie-Dick test:

=>This test is passed if the color of the Bowie-Dick test kit turned uniformly to black having no intermediate color change throughout the entire pattern (e.g. gray, blue or violet) which ensures full vacuum and complete steam penetration.

For Heat Penetration (HP) study:

=>Throughout the sterilization period; all temperatures measured in the chamber has to be within a 4°C band from the set point i.e. 121°C (–1°C/+3°C).
During sterilization period; the difference in temperature between the coolest spot and the mean chamber temperature during sterilization hold period shall be within ±2°C.

For Biological Indicator Test:

=>Biological indicators must have an initial viable spore count of 106 or greater of the selected microorganism.
=>Biological Indicator must not show any growth after autoclaving and subsequent incubation.
=>Positive control biological indicators must show “growth” of Geobacillus Stearothermophilus.
=>The lethality (F0 value) must be equal or greater than 12 minutes.

Deviation And Failure Investigation Summary

In the column below, record any deviations or failures that occurred during the PQ exercise.

Deviation/ Failure No.	Description and Assessment of Impact on Validation	Initial	Date
1
2
3

Reference Documents

[][]SOP for validation of Moist Heat Sterilizer by Biological Indicator.
[][]USP general chapter <1222> Terminal Sterilized Pharmaceutical Products-Parametric release
[][]FDA Guidance for Industry ( for the Submission Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products); November 1994
[][]Practical Guide to Autoclave Validation by Raymond G. Lewis.

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Autoclave Performance Qualification Protocol