10072-02 RQ Protocol Line-1 Tunnel-001

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Details of Equipment/ System

User Department Production

System ID PN/TUNNL-001

Equip. Location/ Room No. Vial washing area Line-1 / PN025

Equip. Make/ Model IMA-LIBRA / BLUE GALAXY 870 FLS

Equip. Serial No. (Supplier) LD 8015

Document Effective Date Qualification Start Date

Qualification Completion Date Requalification due date

Table of Contents

S. No. Details Page No.

1. Pre-Approval 02

2. Scope 03

3. Objective 03

4. Abbreviations 03

5. Responsibility 04

6. Intended use of equipment 04

7. Equipment / system description 04

8. Safety Precautions 05

9. Training Record 05

10. Equipments/ Materials Required for Qualification 06

11. Verification of calibration status 07

12. Verification of operational controls 08

13. Qualification requirements & observations 08

14. Qualification Tests & Results 28

15. Requalification criteria 30

16. Details of Discrepancies 30

17. Summary / Conclusion 31

18. References 32

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TITLE : RE QUALIFICATION PROTOCOL REFERENCE SOP : FU4-QA-GEN-035/ FU4-QA-FORM-120-1

Protocol No.:10072-02 Equipment No.: PN/TUNNL-001

Name Designation Department Signature /date Prepared by

Reviewed by

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This qualification protocol is applicable for the requalification of depyrogenation tunnel in vial washing room of manufacturing Line-1 as per the Qualification Plan 20017.

3. OBJECTIVE:

The objective of this protocol is to ensure the consistency, repeatability and reproducibility of the depyrogenation tunnel machine in the following conditions.

• Measurement of airflow velocity

• Verification of Differential pressures across zones. • Installed filter system integrity / Leakage test. • Air flow pattern test.

• Non-viable particle count. • Verification of Conveyor Speed.

• Heat Penetration Study with biological qualification.

• Heat Penetration Study with biological qualification by increasing set speed. • Physical observation of vials during qualification run.

4. ABBREVIATIONS:

• ID No. - Identification Number • MOC - Material of Construction

• NA - Not Applicable • OQ - Operational Qualification • PQ - Performance Qualification • QA - Quality Assurance • QC - Quality Control • RQ - Re-Qualification

• S. No. - Serial Number

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5. RESPONSIBILITY: Department/

Function Responsibility

Validation

group Preparation & Execution of the protocol and collection of samples. Engineering /

Instrumentation Review the activity and provide required technical support. Quality Control To perform testing of samples, wherever applicable.

User

department To provide necessary support For the execution of activity Quality

Assurance To review and approve the executed protocol with supporting data 6. INTENDED USE OF EQUIPMENT

Depyrogenation tunnel is used for the preparation/processing (depyrogenation) of containers for the filling of sterile drug product. Depyrogenation process shall be done by using filtered dry hot air.

7. EQUIPMENT/ SYSTEM DESCRIPTION

Depyrogenating Tunnel is located at Vial washing room Line-1 of Ground Floor Production Department. The purpose of Depyrogenating Tunnel is to depyrogenate the Vials coming out from the Vial washing Machine. The tunnel, constructed in AISI 304, consists of three laminar flow zones such as inlet zone, heating zone and cooling zone. The clean and slighty containers are arranged and automatically deposited by the washer on to the tunnel conveyor belt at the in-feed zone. The tunnel inlet zone is protected by sterile laminar air flow which protects the washed vials discharged by washing machine and prevents any hot, saturated air, released from the heating zone because of higher pressure. The vials coming out from the heating zone enter into the cooling zone where they struck by the cooling laminar flow and brought to temperature required for the successive working.

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of 50 Pascal with variation of ±15 of such value are absorbed and balanced automatically with out altering the operating parameters.

The tunnel sterilizer equipped with anemometer, DP meters, hot zone air flow measurement system and Automatic adjustment of air speed basing on the density.

8. SAFETY PRECAUTIONS:

• Personnel involved in autoclave qualification shall follow proper written procedures for equipment operation.

• Personnel shall wear necessary gloves, wherever applicable. • Do not touch the hot surfaces during validation.

• Care should be taken while handling with electrical cables. 9. TRAINING RECORD:

Purpose To train all the personnel involved in execution of qualification, on following attributes:

• System Description

• Protocol, applicable SOPs and documentation. Doc. Ref. No(s).

Training by

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10. INSTRUMENT/ MATERIALS REQUIRED FOR QUALIFICATION: 10.1 Details of Instruments

S.

No. Instrument Name Instrument ID

Calibration certificate No./ Done date

Calibration Due date 1

Anemometer IN/ANMTR-001

2 IN/ANMTR-002

3 Digital manometer IN/DMNMR-001 4 Aerosol Photometer IN/APHMR-001 5 Non-Viable particle counter PN/PLCTR-001 6 PN/PLCTR-003 7 PN/PLCTR-004 8 PN/PLCTR-005 9 PN/PLCTR-006 10 Data logger 11 Smoke generator 13 Stop watch Sensor details S.

No. Instrument Name Pre calibration date Post calibration date 1 Temperature mapping probes

Checked By: (Sign and Date)

Reviewed By: (Sign and Date)

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10.2 Details of materials

• Endotoxin spiked container

• Specific size & quantity of the container as per requirement • Minicolt-4 smoke refill canister / Dry Ice

• PAO

11. VERIFICATION OF CALIBRATION STATUS: Equipment

Name Instrument Name Instrument ID No.

Calibration Date Calibration Due Date Tunnel Magnehelic Gauge PN/TUNNL-001-MG001 PN/TUNNL-001-MG002 PN/TUNNL-001-MG003 PN/TUNNL-001-MG004 PN/TUNNL-001-MG005 PN/TUNNL-001-MG006 DP Transmitter PN/TUNNL-001-DPT001 PN/TUNNL-001-DPT002 Temperature Sensor PN/TUNNL-001-TS001 PN/TUNNL-001-TS002 PN/TUNNL-001-TS003 PN/TUNNL-001-TS004 Strip chart Recorder PN/TUNNL-001-SC001 Anemometer PN/TUNNL-001-AM001 PN/TUNNL-001-AM002 PN/TUNNL-001-AM003 Remarks:

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12. VERIFICATION OF OPERATIONAL CONTROLS:

S. No. Description of Control Document Ref. No. Status/ Remarks 1 Availability of approved operation,

cleaning and monitoring SOPs 2 Availability of approved PM SOP 3 Availability of log books for recording

the activities

4 Implementation of gowning practices with SOPs

Remarks: Checked By: (Sign and Date)

Reviewed By: (Sign and Date)

13. QUALIFICATION REQUIREMENTS & OBSERVATIONS: 13.1 Measurement of airflow velocity:

13.1.1 Procedure

• Switch on the tunnel fans in maintenance mode.

• The tunnel should be stabilized at least 15 min prior to start the activity and heaters should be OFF.

• Perform the air velocity measurement test as per SOP # FU4-QA-GEN-040 and record the observations.

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Diagram.1 HEPA Filter location drawing

Diagram.2 Air velocity sampling locations of filter

13.1.2 Acceptance criteria:

Air velocity should be with 79-118 FPM (0.4-0.6 m/s) at conveyer level in infeed zone, hot zone and cool zone.

2

3 4

5 1

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TITLE : PERFORMANCE/ RE QUALIFICATION PROTOCOL REFERENCE SOP : FU4-QA-GEN-035/ FU4-QA-FORM-120-1

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13.2 Verification of Differential pressures across zones: 13.2.1 Procedure :

• Monitor & record the pressure differential values from the calibrated magnehelic gauge across zones.

• Perform the differential pressure test as per SOP # FU4-QA-GEN-040 and record the observations for the various zones using manometer.

• While measuring DP between zone to zone and zone to room, place manometer positive end in high pressure zone and negative in low pressure zone.

Name of the instrument used: Calibration due Date:

Instrument Id: Calibration certificate no:

Filter No

Grill Location & Velocity in m/s

L1 L2 L3 L4 L5 Acc. limit Min

Filter-1 0.4-0.6 m/s Filter-2 Filter-3 Filter-4 Filter-5 Filter-6 Filter-7 Remarks: Done by : (Sign/Date) Checked By: (Sign/Date) Reviewed By: (Sign/Date)

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Diagram .3 Differential pressure representations

13.2.2 Acceptance criteria & Results

Description Acceptance criteria Observation Result Remarks

Filter-1 (Across filter) _{120 pa -350 pa.} _Pass/Fail Filter-2 (Across filter)

120 pa -400 pa.

Pass/Fail

Filter-3 (Across filter) Pass/Fail

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Filter-5 (Across filter) Pass/Fail Filter-6 (Across filter)

120 pa -350 pa.

Pass/Fail

Filter-7 (Across filter) Pass/Fail

DP between Infeed zone

and washing room Infeed zone DP should be higher than washing room Pass/Fail DP between

Depyrogenation zone and Infeed zone

Depyrogenation zone DP should be higher than

Infeed zone Pass/Fail

DP between

depyrogenation zone and cool zone

Depyrogenation zone DP should be higher than cool

zone Pass/Fail

DP between filling

room and cool zone Filling room DP should be higher than cool zone Pass/Fail Done by: (Sign/Date) Checked By: (Sign/Date) Reviewed By: (Sign/Date) Note: √ whichever is correct in result column.

13.3 Installed filter system integrity / Leakage test: 13.3.1 Test Procedure:

• Perform the filter integrity test as per SOP # FU4-QA-GEN-040 and record the observations.

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Filter ID No. _{Concentration %}Upstream _{Concentration %}Downstream Mounting joints_% Result _Sign/Date:Done By

Filter-1 Pass/Fail Filter-2 Pass/Fail Filter-3 Pass/Fail Filter-4 Pass/Fail Filter-5 Pass/Fail Filter-6 Pass/Fail Filter-7 Pass/Fail Remarks if any: Checked by : (Sign / Date) Reviewed by: (Sign / Date) Note: √ whichever is correct in result column.

13.4 Air flow pattern test: 13.4.1 Procedure:

• Ensure that the tunnel air velocities and pressure differential are maintained.

• Perform the air flow pattern test as per SOP # FU4-QA-GEN-040 and record the observations.

• Attach the air flow pattern visual record to the executed protocol.

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Description of test Acceptance criteria Observation Generate the fog near Infeed zone

towards panels

The air flow should be from

Infeed zone to washing room Complies / Not complies Generate the fog in

Depyrogenation zone

The air flow should be towards

Infeed zone and cool zone Complies / Not complies Generate the fog in Filling room

near turn table panel

The airflow should be towards

cooling zone Complies / Not complies Generate the fog near filters in

Infeed zone

Laminarity should be observe until

Working height level. Complies / Not complies Generate the fog near filters in

cooling zone

Laminarity should be observe until

Working height level. Complies / Not complies Remarks:

Checked by : (Sign / Date)

Reviewed by: (Sign / Date) Note: √ whichever is correct in result column.

13.5 Non-viable particle count 13.5.1 Procedure:

• A discrete particle counting, light scattering instrument is used to determine the concentration of air borne particles, equal to and larger than the specified sizes, at designated sampling locations.

• Perform the non viable particle count test as per SOP # FU4-QA-GEN-040and attach the non viable particle count data printout to the executed protocol.

• All the readings of test should pass the below mentioned criteria.

• Maximum permitted number of particles/m3_{is mentioned in following table.}

At rest

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Diagram.5 NVPC location drawing 13.5.3 Results;

Location Observation Results

0.5μm / m3 _{5μm / m}3

Infeed zone location-1 Infeed zone location-2 Infeed zone location-3

Depyrogenation zone location-1 Depyrogenation zone location-2 Depyrogenation zone location-3 Cool zone location-1

Cool zone location-2 Cool zone location-3 Done by Sign/Date

Checked By : (Sign/Date)

Reviewed By : (Sign/Date) 13.6 Verification of conveyor speed :

13.6.1 Procedure:

• Perform the conveyor speed verification for all the set speeds.

• During qualification verification of conveyor speed shall be done as per SOP # FU4-QA-GEN-040.

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• Conveyor speed should be within ± 5% of set speed 13.6.3 Results:

S. No. Container size Set Conveyor _Speed Observed conveyor _Speed Results _{Sign / Date}Done by

Remarks if any:

Checked By:

(Sign/Date ) Reviewed By:(Sign/Date)

13.7 Heat Penetration Study with Endotoxin Spiked Vials 13.7.1 Procedure

• Heat penetration study with endotoxin spiked containers shall be performed for following containers

• 2 mL vial with 13 mm neck • 3 mL vial with 13 mm neck • 5 mL vial with 20 mm neck • 10 mL vial with 20 mm neck

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• The tunnel when operated with fully loaded glass vials on the conveyor is capable of producing the temperature profiles in side the vials distributed across the conveyor belt as per the temperature set points set in the PLC of the equipment.

• Operate the tunnel as per SOP # FU4-PR-MF-OPI-002 & perform the heat penetration study as per SOP # FU4-QA-GEN-040.

• The placement of spiked Endotoxin vials and temperature sensors in empty vial are depicted in the below diagram.

Note: The tunnel conveyor should not stop when SS zigs are in depyrogenation zone Left side conveyor edge

In feed zone Depyrogenation zone Cool zone

Right side conveyor edge

Vial with temperature sensor Endotoxin Spiked Vial

• Each temperature sensor of the row should be more than 300°C for minimum of 3 minutes (Considered as residence time) during Depyrogenation period of each run.

• The temperature variation across all sensors in any row shall not be more than 20°C at any stage in passage of load during calculated residence time.

• Depyrogenation zone temperature during Depyrogenation period shall be at 330 ± 6°C and the same shall be confirmed through strip chart to ensure the equipment functionality. • Minimum 3- log reduction should be achieved for endotoxin spiked vials.

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13.7.3 Results:

Parameters Observations

Results

Container details vial size 2 mL 3mL 5 mL 10 mL 20 mL 30 mL

Neck Size 13 mm 13 mm 20 mm 20 mm 20 mm 20 mm

Date of cycle Cycle Start Time Cycle End Time Set conveyor speed

Observed conveyor speed (max)

Depyrogenation hold start time for set -1 Depyrogenation hold end time for set-1 Calculated residence time for set-1 Depyrogenation hold start time for set -2 Depyrogenation hold end time for set-2 Calculated residence time for set-2 Depyrogenation hold start time for set -3

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Results

Depyrogenation hold end time for set-3 Calculated residence time for set-3 Minimum temperature during depyrogenation hold period for set-1 Maximum temperature during depyrogenation hold period for set-1 Maximum temperature variation across the probes in any row during

Depyrogenation hold period for set-1 Minimum temperature during depyrogenation hold period for set-2 Maximum temperature during depyrogenation hold period for set-2 Maximum temperature variation across

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Results

depyrogenation hold period for set-3 Maximum temperature during depyrogenation hold period for set-3 Maximum temperature variation across the probes in any row during

Depyrogenation hold period for set-3 Maximum variation (± °C) of

temperature from set point (330°C) in strip chart Done by sign/Date Remarks if any: Checked by : (Sign/Date) Reviewed by : (Sign/Date)

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13.8 Heat Penetration Study with Endotoxin Spiked Vials with increased set speed 13.8.1 Procedure:

• Perform the one heat penetration run with endotoxin spiked vials by increasing 5% of set speed and followed same procedure as mentioned in 13.7.1.

13.8.2 Acceptance criteria :

• Each temperature sensor of the row should be more than 300°C for minimum of 3 minutes (considered as residence time) during Depyrogenation period of each run.

• The temperature variation across all sensors in any row shall not be more than 20°C at any stage in passage of load during calculated residence time.

• Depyrogenation zone temperature during Depyrogenation period shall be at 330 ± 6°C and the same shall be confirmed through strip chart to ensure the equipment functionality. • Minimum 3- log reduction should be achieved for endotoxin spiked vials.

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13.8.3 Result:

Results

Date of cycle Cycle Start Time Cycle End Time Actual conveyor speed Increased set conveyor speed Observed conveyor speed (max)

Depyrogenation hold start time for set -1 Depyrogenation hold end time for set-1

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Results

Calculated residence time for set-1 Depyrogenation hold start time for set -2 Depyrogenation hold end time for set-2 Calculated residence time for set-2 Depyrogenation hold start time for set -3 Depyrogenation hold end time for set-3 Calculated residence time for set-3 Minimum temperature during depyrogenation hold period for set-1

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Results

Maximum temperature variation across the probes in any row during

Depyrogenation hold period for set-1 Minimum temperature during depyrogenation hold period for set-2 Maximum temperature during depyrogenation hold period for set-2 Maximum temperature variation across the probes in any row during

Depyrogenation hold period for set-2 Minimum temperature during depyrogenation hold period for set-3 Maximum temperature during depyrogenation hold period for set-3 Maximum temperature variation across the probes in any row during

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Results

Maximum variation (± °C) of

temperature from set point (330°C) in strip chart Done by sign/Date Remarks if any: Checked by : (Sign/Date) Reviewed by : (Sign/Date)

Note-1: If 1 probe gets opened during depyrogenation consider remaining 11 sensors data. At least 11 sensors should be functional throughout the cycle to consider it satisfactorily.

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13.9 Physical observation of vials during heat penetration study: 13.9.1 Procedure:

• Physical observation of the containers shall be done by viewing through the glass window of the tunnel (cool zone) for following parameters.

• Movement of the vial, tilting of vial on conveyor, breakage of the vial, charring of the vial.

13.9.2 Acceptance criteria & Results: S.No. Parameters / Acceptance criteria Observation 2 mL 3mL 5mL 10mL 20mL 30mL 1

Vial should move on the conveyor belt in erect condition. No vial should be tilted 2 No breakage of vials _{should be observed}

3

No charring spot should be observed on the surface of the vials 4 Observed by sign /date Remarks if any: Checked by Sign/Date : Reviewed by Sign/Date :

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14 QUALIFICATION TESTS & RESULTS:

S. No. Test Item/ Stage

Refere nce Docum ent No.

Acceptance Criteria Results

Si gn & D at e Measurement of Air flow

velocity

SOP #

FU4-QA-GEN-040 Refer point no.13.1.2 Differential pressure test _QA-GEN-040SOP # FU4- Refer point no.13.2.2 Filter integrity / Leakage

test

SOP #

FU4-QA-GEN-040 Refer point no.13.3.2 Air flow pattern test _QA-GEN-040SOP # FU4- Refer point no.13.4.2 Non viable particle _QA-GEN-040SOP # FU4- Refer point no.13.5.2

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FU4-TITLE : RE QUALIFICATION PROTOCOL REFERENCE SOP : FU4-QA-GEN-035/ FU4-QA-FORM-120-1

S. No. Test Item/ Stage

Refere nce Docum ent No.

Acceptance Criteria Results

Si gn & D at e with Endotoxin spiked

vials QA-GEN-040

Heat penetration study with Endotoxin spiked vials with increased set speed

NA Refer point no.13.8.2 Physical observation of

vials during Heat penetration study

SOP #

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15 REQUALIFICATION CRITERIA 15.1 Scheduled re-qualification:

• Heat Penetration and Endotoxin challenge trials shall be done as part of a time-related re-qualification programme for every tunnel.

• Re-qualification shall be performed once in six months at minimum.

• One heat penetration with endotoxin challenge trail shall be done on every process specification / container size combination on each tunnel at least once per 2-years.

• Where HEPA filter in situ integrity testing in the hot zone of LAF tunnels is required to be done twice per year at approximately 6 month intervals.

15.2 Unscheduled re-qualification:

• Any modification in the depyrogenation process parameters or any major maintenance of equipment which has impact on depyrogenation, shall be properly investigated. Based on out come of the investigation results requalification shall be performed.

• Introduction of any new container (specifications/source) shall be qualified, based on the impact assessment on the depyrogenation efficiency.

16 DETAILS OF DISCREPANCIES: Description Notification Ref. No. Proposed/ Performed Corrective Actions Recorded By (Sign and Date)

Impact on Qualification/ Further Actions to be taken (if any):

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17 SUMMARY/ CONCLUSION:

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18 REFERENCES:

• SOP # FU4-QA-GEN-040 - Qualification/ Re-Qualification of Depyrogenation Tunnel • SOP # FU4-PR-MF-OPI-002 - Cleaning and Operation of Depyrogenating Tunnel

(Make-IMA).

• SOP # FU4-EN-OPI-007- Operation of digital temperature data logger.

• SOP # FU4-QC-MIC-GEN-029 - Handling and Maintenance of Endotoxin Indicators

19 ANNEXURES:

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20 POST APPROVAL:

Name Designation Department Signature/ Date Executed by

Reviewed by