10072-02 rq protocol line-1 tunnel-001

TITLE : RE QUALIFICATION PROTOCOL

REFERENCE SOP : FU4-QA-GEN-035/ FU4-QA-FORM-120-1

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

Details of Equipment/ System

User Department ProductionSystem ID PN/TUNNL-001Equip. Location/ Room No. Vial washing area Line-1 / PN025Equip. Make/ Model IMA-LIBRA / BLUE GALAXY 870 FLSEquip. Serial No. (Supplier) LD 8015Document Effective DateQualification Start DateQualification Completion DateRequalification due date

Table of Contents

S. No. Details Page No.

1. Pre-Approval 022. Scope 033. Objective 034. Abbreviations 035. Responsibility 046. Intended use of equipment 047. Equipment / system description 048. Safety Precautions 059. Training Record 0510. Equipments/ Materials Required for Qualification 0611. Verification of calibration status 0712. Verification of operational controls 0813. Qualification requirements & observations 0814. Qualification Tests & Results 2815. Requalification criteria 3016. Details of Discrepancies 3017. Summary / Conclusion 3118. References 3219. Annexure 3220. Post Approval 33

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Formulations Unit-IV, AUROBINDO PHARMA LIMITED, Plot No’s - 4, 34 to 48, EPIP, IP-Pashamylaram, Medak(Dist.), Hyderabad – 502307




1. PRE APPROVAL:

Name Designation Department Signature /date

Prepared by

Reviewed by

Approved by

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2. SCOPE:

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

PN - Production

AISI - American Iron And Steel Institute

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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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With the principle of communicating vessel, assisted by the make up of the hot zone tunnel

permits operation with difference in pressure between the sterile chamber and the tunnel area

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

S. No. Name of the participant Area of Operation Sign and Date

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Trainer (Sign and Date):

10. INSTRUMENT/ MATERIALS REQUIRED FOR QUALIFICATION:

10.1 Details of Instruments

S. No.

Instrument Name Instrument IDCalibration certificate

No./ Done dateCalibration Due

date

1Anemometer

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 datePost calibration

date

1 Temperature mapping probesChecked 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

DateCalibration 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 TransmitterPN/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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Equipment Name

Instrument Name Instrument ID No.Calibration

DateCalibration Due Date

Checked By:(Sign and Date)

Reviewed By:(Sign and Date)

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 activities4 Implementation of gowning practices

with SOPsRemarks:

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.

Calculate minimum, maximum & average velocity of all locations.

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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.

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2

34

5

1

TITLE : PERFORMANCE/ RE QUALIFICATION PROTOCOL



13.1.3 Result:

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 Max Average

Filter-1

0.4-0.6 m/s

Filter-2

Filter-3

Filter-4

Filter-5

Filter-6

Filter-7

Remarks:

Done by : Checked By: Reviewed By:

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TITLE : PERFORMANCE/ RE QUALIFICATION PROTOCOL



(Sign/Date) (Sign/Date) (Sign/Date)

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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.

Diagram .3 Differential pressure representations

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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



Filter-6 (Across filter)120 pa -350 pa.

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.

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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.


The downstream concentration of aerosol from each HEPA filter should not be more than 0.01%, while upstream PAO concentration is set as 100%.

13.3.3 Results:

Filter ID No.Upstream

Concentration %Downstream

Concentration %Mounting joints

%Result Done By

Sign/Date:

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)


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.

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

13.4.2 Acceptance criteria & Results

Description of test Acceptance criteria Observation

Generate the fog near Infeed zone towards panels

The air flow should be fromInfeed 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)


13.5 Non-viable particle count

13.5.1 Procedure:

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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-040 and 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

Maximum permitted number of particles/m3

0.5μm/ m3 5μm/ m3

≤ 3520 ≤ 20

Diagram.5 NVPC location drawing

13.5.3 Results;

Location Observation Results

0.5μm / m3 5μm / m3

Infeed zone location-1



Depyrogenation zone location-1



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Cool zone location-1



Done by Sign/DateChecked 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.

Operate the tunnel as per SOP # FU4-PR-MF-OPI-002


Conveyor speed should be within ± 5% of set speed

13.6.3 Results:

S. No. Container sizeSet Conveyor

SpeedObserved conveyor

SpeedResults

Done by Sign / Date

Remarks if any:

Checked By:(Sign/Date )

Reviewed By:(Sign/Date)

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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





30mL vial with 20 mm neck

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

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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

ResultsContainer 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



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Calculated residence time for set-3Minimum temperature during depyrogenation hold period for set-1Maximum temperature during depyrogenation hold period for set-1Maximum temperature variation across the probes in any row during Depyrogenation hold period for set-1Minimum temperature during depyrogenation hold period for set-2Maximum temperature during depyrogenation hold period for set-2Maximum temperature variation across the probes in any row during

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Neck Size 13 mm 13 mm 20 mm 20 mm 20 mm 20 mmDepyrogenation hold period for set-2Minimum temperature during depyrogenation hold period for set-3Maximum temperature during depyrogenation hold period for set-3Maximum temperature variation across the probes in any row during Depyrogenation hold period for set-3Maximum variation (± °C) of temperature from set point (330°C) in strip chartDone 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:





Date of cycle

Cycle Start Time

Cycle End Time

Actual conveyor speed

Increased set conveyor speed

Observed conveyor speed (max)



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Minimum temperature during depyrogenation hold period for set-1Maximum temperature during

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depyrogenation hold period for set-1Maximum temperature variation across the probes in any row during Depyrogenation hold period for set-1Minimum temperature during depyrogenation hold period for set-2Maximum temperature during depyrogenation hold period for set-2Maximum temperature variation across the probes in any row during Depyrogenation hold period for set-2Minimum temperature during depyrogenation hold period for set-3Maximum temperature during depyrogenation hold period for set-3Maximum temperature variation across

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the probes in any row during Depyrogenation hold period for set-3Maximum variation (± °C) of temperature from set point (330°C) in strip chartDone 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

2No breakage of vials should be observed

3

No charring spot should be observed on the surface of the vials

4Observed 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/ StageReference

Document No.Acceptance Criteria Results

Sign & Date

1. Measurement of Air flow velocity

SOP # FU4-QA-GEN-040

Refer point no.13.1.2

2.Differential pressure test



3. Filter integrity / Leakage test



4.Air flow pattern test



5.Non viable particle



6. Verification of conveyor speed



7. Heat penetration study with Endotoxin spiked



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S. No. Test Item/ StageReference

Document No.Acceptance Criteria Results

Sign & Date

vials

8.Heat penetration study with Endotoxin spiked vials with increased set speed

NA Refer point no.13.8.2

9.Physical observation of vials during Heat penetration study



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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 ActionsRecorded By

(Sign and Date)

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

Reviewed By (User):(Sign and Date)

Approved By (QA):(Sign and Date)

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17 SUMMARY/ CONCLUSION:

Prepared by: Reviewed by:

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Sign/Date : Sign/Date :

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:

S. No. Title/ Description of Annexure No. of Pages

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20 POST APPROVAL:

Name Designation Department Signature/ Date

Executed by

Reviewed by

Approved by

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10072-02 rq protocol line-1 tunnel-001

Documents

biological qualification

qualification plan

qualification tests

depyrogenation tunnel

equipment system description04

executed protocol

room line

depyrogenation process