Investigation of incident


(Ravi) #21

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(YOGESH NARKHEDE) #22

Annexure - III
Investigation Report Format
Purpose:
Purpose of this incident investigation report is to identify the probable root cause for observed leak test failure product Esomezol 40 batch number A04621801 and to suggest the suitable corrective and preventive action.
Scope:
This investigation report is applicable to following
Product name: Esomezol 40
Generic Name: Esomeprazole DR Capsules 40 mg
Batch number: A04621801
Mfg. date: Sep.2018
Exp. Date: Aug. 2020
Planned Batch size: 245000 capsules
Background:
Esomezol 40 is Encapsulated on AF 90 machine & packing activity on strip pack machine PR047. Above mentioned batch packing was started on strip pack Machine (PR047) on dated 01/Oct/2018.During strip packing, while carrying out in-process checks by IPQA, leak test was found failed .The incidence was reported during shipper number 13 on dated 02/Oct/2018, So strip packing activity was stopped and leak test of previous packed shipper from 12 to 01 were checked.
Leak test of strips collected from shipper no.05,09,10,11,12, were found failed & strip collection from shipper no. 01,02,03,04,06,07,08 were found Pass. Hence the leak test failed from shipper No. 05 to 13 were send for defoiling Hence this incident investigation report is initiated to find out probable root cause and to suggest suitable corrective and preventive action for the observation of leak test failure.
Investigation:

  1. Product Esomezol 40 packing activity was initiated on Strip pack machine (Make: Sattelite Equipment ID PR 047) on Date: 01/Oct/2018 at 21:55 hrs. in second shift by Operator Mr. Mohan B. At the start of the batch initially leak test was passed.
  2. In the third shift machine was idle.
    SOP Ref. No. : CQ/003 Page 2 of 3
    Format No.: CQ/003/F-03
  3. On the next day 02/Oct/2018 batch packing activity initiated at 07:25 hrs. by operator Chandrakant K., initially leak test was passed. After one and half an hour leak test failure observed.
  4. Change part of layout number SE-1083, pack size 52 mm X 175 mm. Same Change part was used for previous batch.
  5. There were three rolls of Printed Al. Foil and two rolls of plain silver Al. Foil. Issued for this batch.
  6. At first Printed Al. Foil roll of 6.710 Kg was loaded on strip pack machine for packing.
  7. Parameters set and recorded during packing activity were as follows.
    Sr. No
    Parameter
    Standard
    Observation

Temperature of sealing Roller/ Plate (℃)
140 to 160 ℃
143 to 144 ℃
2.
Speed of machine (Cuts/min)
45 – 65 cuts/min
45.10 to 46.15 cuts/min
3.
Air Pressure (Kg/cm2)
4 to 6 Kg/cm2
5 Kg/cm2
8. performance checks for Strip pack machine was done as per defined procedure in BPR and found satisfactory result.
9. During In-process checking, IPQA observed leak test failure. At that time packing of shipper No. 13 was going on. Machine was stopped.
10. Leak test from remaining all shippers were checked and observed that shipper No.05,09,10,11,12, were failed for leak test & shipper no. 01,02,03,04, 06,07,08 were found Passes. Hence the leak test failed from shipper no. 05 to 13 were send for defoiling.
11. No breakdown was observed during machine operation.
10 Both the printed Al. Foil and Plain silver Al. foil were approved by QC before use.
In this batch total 39 shippers were packed and no leak test failure was observed after shipper No.13.
11 During investigation it was observed that foil roll was changed when shipper No. 06 packing was going on. At that time sealing roller was cleaned by operator and leak test was passing.
SOP Ref. No. : CQ/003 Page 3 of 3
Format No.: CQ/003/F-03
12 At the end of Al foil roll there might be improper tightness of Al. foil and shifting of sealing roller resulting in failure of leak test in shipper No. 05. Also there was collection of strips in secondary packing area and this collection was packed in shipper No. 09. 10. 11 and 12 hence leak test of these shippers were failed.
13 Due to improper tightness of Al Foil and sifting of sealing roller at the end of Al foil roll, foil burr was accumulated on the surface of sealing roller and was not noticed by Operator during machine run, resulting into failure of leak test.
Root Cause:
Personnel Failure.

  1. Burr observed on sealing Roller was not noticed by operator during machine run.
  2. Machine setting.
    Corrective Action:
  3. Strips from shipper No. 05 to 13 to be defoiled and good inspected strips to be packed.
  4. Operator to notice the cleaning of sealing roller during machine run, retraining shall be imparted to all concerned personnel.
    Risk Analysis:
    Strips from leak test failed shippers were defoiled and only good inspected strips were allowed for packing. Also no leak test failure observed after shipper No. 13 till completion of batch, hence no risk to the quality of product
    Preventive Action:
  5. Already sealing roller cleaning and its recording provision is available, concerned operator has to ensure proper cleaning of sealing roller and shall be more vigilant during machine operation.
    Prepared By: Reviewed By: Approved By

(YOGESH NARKHEDE) #23

Annexure III
Investigation Report Format
Purpose:
Purpose of this annexure is to investigate the less yield at compression stage of Starvog M 0.3 B NO. M12DE18005
Scope:
The Scope of this annexure is applicable For Starvog M 0.3 B NO. M12DE18005
Background
At compression stage during reconciliation it was observed that the % yield of batch was 89.51 % against the standards yield limit NLT 90 %.
Investigation:
Following are the reconciliation details.
1
Planned theoretical batch size : 540.75 kg ≈ 515000 tablets
2
Calculated theoretical yield (Kg) :536.915 kg ≈511347
3
Actual Quantity transferred for next stage: (Kg) 477.595 kg ≈ 454030 Nos
4
Sample Quantity (a+b+c)
Kg
No
a) In process Sample
2.417
2298
b) QC Sample
0.158
150 Tablets
c) Other sample during compression
-200 gm Metformin
-200gmVoglibose
-380
Total (a+b+c)
2.975
2828
5
Handling Waste (d+e+f) = 53.775 kg
d) Metformin HCL SR granules left over in Kg: 25.635 kg
e) Voglibose granules Left over in kg : 0.900
f) Reject (i+ii+iii)
Sr. no.
Qty of Tablet rejected
Kg
No.
i)
During compression
1.190®+1.500ˣ+12.250•
14202
ii)
During Inspection

iii)
Other rejection
12.300 ˣ ˣ

6
Total Rejects = Step 5 + a = 56.192 kg
7
% Standard Yield {( Step 3+Step 4) / Step 2 X100 } = 89.51 %
Range for % yield = NLT 90 %
8
% Reconciliation {(Step 3 + Step 4 + Step 5) / Step 2 X 100} = 99.52 %
®-Initial layer 1 rejection -1.190 kg, ˣ-Initial rejection layer 2-1.500 kg,•In process rejection due to hardness problem setting done at different speed hence rejection generated 12.250 kg, ˣ ˣ - Voglibose Dust 12.30 kg
SOP Ref. No.: CQ/003 Page 2 of 2
Format No.: CQ/003/F-03
During initial setting at compression stage, at 35 RPM of tablet compression machine, maximum hardness was achieved to 12.00 Kp, hence speed reduced to 25 and maximum hardness was observed 12.80 kp and minimum 9.40 Kp, then speed reduced to 20 RPM maximum hardness was observed 14.30 kp and minimum hardness was 8.20 kp, at these speed i.e. 35, 25 and 20 RPM hardness failed to achieve desired specification i.e. 12.0 Kp to 35.0 Kp hence speed was reduced to 16 RPM, at this RPM i.e. 16 RPM all parameters are found well within the specified limit mentioned in BMR. During this setting for hardness rejection of tablets generated i.e. 12.250 kg ≈ 2.28 % against transferred quantity of granulation stage , hence yield impacted .
Root Cause:
To achieved desired hardness speed was reduced at different RPM (35,25,20,16 rpm ) hence more rejection generated and it impacted on yield .
Corrective Action:
Rejected tablets sent to solid waste destruction .
Risk Analysis:
Good tablets transferred to next stage hence there is no risk anticipated .
Preventive Action:
Preventive action can be suggested upon completion of detailed investigation of respective incident .
Prepared By: Reviewed By: Approved By


(YOGESH NARKHEDE) #24

Annexure - III
Investigation Report Format I/PR/18/195

Purpose:
Purpose of this incident investigation report is to identify the probable root cause for observed broken tablets in product Metformin HCL ER Tablets USP 500 mg batch number 03118300 and to suggest the suitable corrective and preventive action.
Scope:
This investigation report is applicable to following
Product: Metformin HCL ER Tablets USP 500 mg
Batch No. : 03118300
Batch Size : 925000 Nos.
Mfg. Date : Sep.2018
Exp. Date : Aug.2020
Count : 500’s HDPE
Market : USA
Equipment Name : Countec Bottle pack machine

Background: Product Metformin HCL ER Tablets USP 500 mg is manufactured by Inventia for USA Market. Manufacturing stages of Metformin HCL ER Tablets USP 500 mg involves milling, dry mixing, wet granulation, drying, sizing, lubrication and compression and inspection and then batch transfer for packing. Packing activity was performed on Countec Bottle pack machine. During packing of above said batch, broken tablets were observed in HDPE container, hence packing activity stopped immediately. This was the First batch after product change over on 29 station XL 400 compression machine ( PR040). There were total 54 drums in the batch. During primary packing broken tablets were observed in drum during primary packing. 37 No. of drums were remained for packing. 17 containers were packed. Previously there was such observation during packing of the batch. As a investigation composite sample of 20 tablets from three drums was taken and checked for thickness and hardness and observed that thickness of all tablets was well within the limit and for hardness out of 20 tablets only two tablets hardness observed on lower side i.e. 12.9 kp and 12.7 kp ( Limit: 13 to 23 kp), Therefore this incidence investigation report is initiated to find out the probable root cause and to suggest suitable corrective and preventive action plan and to evaluate the impact.

Ishikawa (Fish bone diagram) was drawn come to investigation:

Training Qualification

Machine setting Preventive /Breakdown
Maintenance
Lack of knowledge
Temperature /RH In-process testing equipments
In area
In process Test parameters

                                                           Release Status	      In process Controls
                                                                                                                                        In process test Parameter 

                                                               
                       Particle size distribution                                                  Wet granulation in RMG 1200 L

Investigation:

  1. Investigation related to Persons:

All operators & supervisors involved in manufacturing and packing activity were trained and competent.

  1. Investigation related Environment:
    Temperature, humidity conditions in manufacturing areas were found to be well within specified limits of 19 to 27 deg C and 40 to 65% RH.

  2. Investigation related to equipment and measurement:
    All the Equipments involved in manufacturing and packing activity were in qualified status. Preventive maintenance and calibration were performed as per scheduled frequency. Hardness tester breakdown was observed on 24/Nov/2018 at 01 hr. 20 min. During breakdown period, samples for hardness were checked on IPQA office hardness tester and results were found satisfactory. After rectification calibration of hardness tester was performed before use.

  3. Investigation related to Method:
     Manufacturing stages of Metformin HCL ER Tablets USP 500 mg involves milling, dry mixing, wet granulation, drying, sizing, lubrication and compression and inspection and then batch transfer for packing.
     Packing activity was performed on Countec Bottle pack machine. During packing of above said batch, broken tablets were observed in HDPE container, hence packing activity stopped immediately.
     Granulation activity was performed on RMG 1200 L by wet granulation, drying in FBD 1300 and lubrication octagonal blender 2000 L.
     This was the First batch after product change over on 29 station XL 400 compression machine ( PR040). There were total 54 drums in the batch. During primary packing broken tablets were observed in drum during primary packing. 37 No. of drums were remained for packing. 17 containers were packed. Previously there was such observation during packing of the batch.
     As a investigation composite sample of 20 tablets from three drums was taken and checked for thickness and hardness and observed that thickness of all tablets was well within the limit and for hardness out of 20 tablets only two tablets hardness observed on lower side i.e. 12.9 kp and 12.7 kp ( Limit: 13 to 23 kp)

 Product Metformin HCL ER Tablets USP 500 mg packing activity was initiated on Countec Bottle pack machine on Date: 01/Oct/2018 at 13:35 hrs.
 Performance checks for Countec Bottle Machine was done as per defined procedure in BPR and was satisfactory.
 Tablets were stored in blue HDPE drums. In one drum total 15 Kg tablets (three polybags each of 5 kg) were stored due to unavailability of white drums.
 There were total 54 drums in the batch. During primary packing broken tablets were observed in drum during primary packing. 37 No. of drums were remained for packing.
 Tablets hardness and all remaining in-process checking parameters were well within the limit during the compression activity.
 During investigation it was observed that there was void space remaining after container filling.
 Three polybags were stored in HDPE container one above the other. In the polybag which was kept at the bottom, there is possibility of breaking of tablets due to weight of tablets in the upper polybags.
 Tablets might have broken due to weight of above tablets during handling of containers. Remaining batch (37 Drums) was inspected for defect on enclony tablet inspection machine ( PR438) and 5.250 kg ( 0.90 %) rejection was observed.
 Total 350 crack tablets and 1660 edge crack tablets were observed.
 9.0 Kg tablets recovered from the rejection defoiling. It may impact yield of the batch.
 During investigation it was observed that there was void space remaining after container filling. Three polybags were stored in HDPE container one above the other. In the polybag which is kept at the bottom, there is possibility of breaking of tablets due to weight of tablets in the upper polybags. Tablets might have broken due to weight of above tablets during handling of containers.
 total 147 shippers ( 147 X 12 X 500 Tablets) were packed. 9.0 Kg tablets recovered from the rejection defoiling. It may impact yield of the batch. Only good tablets were allowed for packing and batch will be released only after complying finished product specification, hence no impact on product quality

  1. Investigation related to material:
     All the raw materials used in the batch were in approved state at the time of dispensing.
     All granulation parameters were observed well within the limit , also found comparable with other batches compressed on 29 station Korsch XL 400 machine ( ID No. PR040).- Refer attached data for details.
     Metformin API (Material code :1000243) of Batch No.: 000065948; AR No. 10000250660) was used in the particle size of the API ( metformin HCL – Harman) used in the batch was observed as follows.

Test Specification Observation
Particle Size ( By Malvern master Sizer) D (0.1) NMT 20 micron D (0.1) 5 micron
D (0.5) NMT 50 micron D (0.5) 34 micron
D (0.9) NMT 100 micron D (0.9) 72 micron

 Compression machine was run at the speed of with the standard speed 40 RPM
During compression machine was stopped at 01:10 hrs. on dt: 28/Sep/2018 due to hardness tester error. Tablets hardness was checked on hardness tester from IPQA room and results were satisfactory.
 Again machine was stopped at 03:20 on the same day due to roller heater problem and low hydraulic pressure, machine was rectified and again started.
 Friability observed in the range of 0.043 % to 0.129 % w/w ( Limit: NMT 1 % w/w).
 Hardness observed in the range of 13.00 to 17.05 kp ( Limit: 13 Kp to 23 Kp).
 As a part of investigation 10 containers were sampled and tested for hardness and friability as per protocol No. MISP/QA/0021. Observations were as follows.
 Hardness observations were as follows:

 	Hardness data

Batch No. Shipper No. Min Max
03118300 70 12.4 14.4
29 12.6 15.6
56 12.9 15.5
1 13.1 15.8
14 14.2 16.9
147 13.6 16.4
84 13.2 17.2
42 12.9 15.5
133 13.1 16.0
109 13.1 16.1
Min 12.4 14.4
Max 14.2 17.2

Remark- Out of ten shipper samples four sample hardness observed below the limit, hence it is decided to check friability of samples.
B. No. Shipper No. Friability (%) Limit: NMT 1 %
3118300 70 0.143
29 0.221
56 0.166
1 0.265
14 0.104
147 0.162
84 0.175
42 0.174
133 0.181
109 0.197
Min 0.104
Max 0.265
Average 0.179

Remark- From the above table it is clear that friability observed is well within the limit.
Previous batches trend for friability was observed as follows.

% Friability
% Friability

Min 0.00
Max 0.378
Average 0.166

Hence friability of this batch found comparable with trend of previous batches.
Root Cause:
Tablets may have broken due to

  1. Hardness of tablets observed on lower side.
  2. Due to weight of upper tablets on lower tablets in blue HDPE drums during handling.

Corrective Action:

  1. Only good tablets are allowed for packing after inspection.
  2. Batch to be released after complying finished product release specification.

Risk Analysis:

Friability of tablets is passing, hence risk of tablets breakage during transportation is minimized. Only good tablets were allowed for packing after inspection, also being bulk container pack, during dispensing broken tablets can be easily identified visually and patient will receive good intact tablet, hence no risk to the patient’s safety and quality of product.

Preventive Action:

  1. It is recommended to use white drum for storing tablets wherein very less space is remaining after tablets filling.

Prepared By: Reviewed By: Annexure - III
Investigation Report Format I/PR/18/195

Purpose:
Purpose of this incident investigation report is to identify the probable root cause for observed broken tablets in product Metformin HCL ER Tablets USP 500 mg batch number 03118300 and to suggest the suitable corrective and preventive action.
Scope:
This investigation report is applicable to following
Product: Metformin HCL ER Tablets USP 500 mg
Batch No. : 03118300
Batch Size : 925000 Nos.
Mfg. Date : Sep.2018
Exp. Date : Aug.2020
Count : 500’s HDPE
Market : USA
Equipment Name : Countec Bottle pack machine

Background: Product Metformin HCL ER Tablets USP 500 mg is manufactured by Inventia for USA Market. Manufacturing stages of Metformin HCL ER Tablets USP 500 mg involves milling, dry mixing, wet granulation, drying, sizing, lubrication and compression and inspection and then batch transfer for packing. Packing activity was performed on Countec Bottle pack machine. During packing of above said batch, broken tablets were observed in HDPE container, hence packing activity stopped immediately. This was the First batch after product change over on 29 station XL 400 compression machine ( PR040). There were total 54 drums in the batch. During primary packing broken tablets were observed in drum during primary packing. 37 No. of drums were remained for packing. 17 containers were packed. Previously there was such observation during packing of the batch. As a investigation composite sample of 20 tablets from three drums was taken and checked for thickness and hardness and observed that thickness of all tablets was well within the limit and for hardness out of 20 tablets only two tablets hardness observed on lower side i.e. 12.9 kp and 12.7 kp ( Limit: 13 to 23 kp), Therefore this incidence investigation report is initiated to find out the probable root cause and to suggest suitable corrective and preventive action plan and to evaluate the impact.

Ishikawa (Fish bone diagram) was drawn come to investigation:

Training Qualification

Machine setting Preventive /Breakdown
Maintenance
Lack of knowledge
Temperature /RH In-process testing equipments
In area
In process Test parameters

                                                           Release Status	      In process Controls
                                                                                                                                        In process test Parameter 

                                                               
                       Particle size distribution                                                  Wet granulation in RMG 1200 L

Investigation:

  1. Investigation related to Persons:

All operators & supervisors involved in manufacturing and packing activity were trained and competent.

  1. Investigation related Environment:
    Temperature, humidity conditions in manufacturing areas were found to be well within specified limits of 19 to 27 deg C and 40 to 65% RH.

  2. Investigation related to equipment and measurement:
    All the Equipments involved in manufacturing and packing activity were in qualified status. Preventive maintenance and calibration were performed as per scheduled frequency. Hardness tester breakdown was observed on 24/Nov/2018 at 01 hr. 20 min. During breakdown period, samples for hardness were checked on IPQA office hardness tester and results were found satisfactory. After rectification calibration of hardness tester was performed before use.

  3. Investigation related to Method:
     Manufacturing stages of Metformin HCL ER Tablets USP 500 mg involves milling, dry mixing, wet granulation, drying, sizing, lubrication and compression and inspection and then batch transfer for packing.
     Packing activity was performed on Countec Bottle pack machine. During packing of above said batch, broken tablets were observed in HDPE container, hence packing activity stopped immediately.
     Granulation activity was performed on RMG 1200 L by wet granulation, drying in FBD 1300 and lubrication octagonal blender 2000 L.
     This was the First batch after product change over on 29 station XL 400 compression machine ( PR040). There were total 54 drums in the batch. During primary packing broken tablets were observed in drum during primary packing. 37 No. of drums were remained for packing. 17 containers were packed. Previously there was such observation during packing of the batch.
     As a investigation composite sample of 20 tablets from three drums was taken and checked for thickness and hardness and observed that thickness of all tablets was well within the limit and for hardness out of 20 tablets only two tablets hardness observed on lower side i.e. 12.9 kp and 12.7 kp ( Limit: 13 to 23 kp)

 Product Metformin HCL ER Tablets USP 500 mg packing activity was initiated on Countec Bottle pack machine on Date: 01/Oct/2018 at 13:35 hrs.
 Performance checks for Countec Bottle Machine was done as per defined procedure in BPR and was satisfactory.
 Tablets were stored in blue HDPE drums. In one drum total 15 Kg tablets (three polybags each of 5 kg) were stored due to unavailability of white drums.
 There were total 54 drums in the batch. During primary packing broken tablets were observed in drum during primary packing. 37 No. of drums were remained for packing.
 Tablets hardness and all remaining in-process checking parameters were well within the limit during the compression activity.
 During investigation it was observed that there was void space remaining after container filling.
 Three polybags were stored in HDPE container one above the other. In the polybag which was kept at the bottom, there is possibility of breaking of tablets due to weight of tablets in the upper polybags.
 Tablets might have broken due to weight of above tablets during handling of containers. Remaining batch (37 Drums) was inspected for defect on enclony tablet inspection machine ( PR438) and 5.250 kg ( 0.90 %) rejection was observed.
 Total 350 crack tablets and 1660 edge crack tablets were observed.
 9.0 Kg tablets recovered from the rejection defoiling. It may impact yield of the batch.
 During investigation it was observed that there was void space remaining after container filling. Three polybags were stored in HDPE container one above the other. In the polybag which is kept at the bottom, there is possibility of breaking of tablets due to weight of tablets in the upper polybags. Tablets might have broken due to weight of above tablets during handling of containers.
 total 147 shippers ( 147 X 12 X 500 Tablets) were packed. 9.0 Kg tablets recovered from the rejection defoiling. It may impact yield of the batch. Only good tablets were allowed for packing and batch will be released only after complying finished product specification, hence no impact on product quality

  1. Investigation related to material:
     All the raw materials used in the batch were in approved state at the time of dispensing.
     All granulation parameters were observed well within the limit , also found comparable with other batches compressed on 29 station Korsch XL 400 machine ( ID No. PR040).- Refer attached data for details.
     Metformin API (Material code :1000243) of Batch No.: 000065948; AR No. 10000250660) was used in the particle size of the API ( metformin HCL – Harman) used in the batch was observed as follows.

Test Specification Observation
Particle Size ( By Malvern master Sizer) D (0.1) NMT 20 micron D (0.1) 5 micron
D (0.5) NMT 50 micron D (0.5) 34 micron
D (0.9) NMT 100 micron D (0.9) 72 micron

 Compression machine was run at the speed of with the standard speed 40 RPM
During compression machine was stopped at 01:10 hrs. on dt: 28/Sep/2018 due to hardness tester error. Tablets hardness was checked on hardness tester from IPQA room and results were satisfactory.
 Again machine was stopped at 03:20 on the same day due to roller heater problem and low hydraulic pressure, machine was rectified and again started.
 Friability observed in the range of 0.043 % to 0.129 % w/w ( Limit: NMT 1 % w/w).
 Hardness observed in the range of 13.00 to 17.05 kp ( Limit: 13 Kp to 23 Kp).
 As a part of investigation 10 containers were sampled and tested for hardness and friability as per protocol No. MISP/QA/0021. Observations were as follows.
 Hardness observations were as follows:

 	Hardness data

Batch No. Shipper No. Min Max
03118300 70 12.4 14.4
29 12.6 15.6
56 12.9 15.5
1 13.1 15.8
14 14.2 16.9
147 13.6 16.4
84 13.2 17.2
42 12.9 15.5
133 13.1 16.0
109 13.1 16.1
Min 12.4 14.4
Max 14.2 17.2

Remark- Out of ten shipper samples four sample hardness observed below the limit, hence it is decided to check friability of samples.
B. No. Shipper No. Friability (%) Limit: NMT 1 %
3118300 70 0.143
29 0.221
56 0.166
1 0.265
14 0.104
147 0.162
84 0.175
42 0.174
133 0.181
109 0.197
Min 0.104
Max 0.265
Average 0.179

Remark- From the above table it is clear that friability observed is well within the limit.
Previous batches trend for friability was observed as follows.

% Friability
% Friability

Min 0.00
Max 0.378
Average 0.166

Hence friability of this batch found comparable with trend of previous batches.
Root Cause:
Tablets may have broken due to

  1. Hardness of tablets observed on lower side.
  2. Due to weight of upper tablets on lower tablets in blue HDPE drums during handling.

Corrective Action:

  1. Only good tablets are allowed for packing after inspection.
  2. Batch to be released after complying finished product release specification.

Risk Analysis:

Friability of tablets is passing, hence risk of tablets breakage during transportation is minimized. Only good tablets were allowed for packing after inspection, also being bulk container pack, during dispensing broken tablets can be easily identified visually and patient will receive good intact tablet, hence no risk to the patient’s safety and quality of product.

Preventive Action:

  1. It is recommended to use white drum for storing tablets wherein very less space is remaining after tablets filling.

Prepared By: Reviewed By:


(YOGESH NARKHEDE) #26


(YOGESH NARKHEDE) #27

Annexure - III
Investigation Report for I/PR/18/194
Purpose:
Purpose of this investigation is to identify the root cause and to determine appropriate corrective and preventive actions for observed one partially sealed bottle during Online AQL inspection of shipper no. 25 and sachet embedded in sealing in bottle of shipper number 26 during packing of product Duloxetine Delayed release capsules USP 30 mg.

Scope:
This is applicable to product Duloxetine Delayed Release capsules USP 30 mg.
Batch number: 00818007
Pack size: 90 capsules in bottle pack
Mfg. date: Jul.2018
Exp. date: Jun.2020
Batch size: 132.55 kg ~ 701323 capsules

Background:
Product Duloxetine Delayed Release capsules USP 30 mg is manufactured and packed for US Market at Inventia Healthcare Limited. Required quantities of packing materials were issued as per batch requirement.
Bulk packing activity was initiated on countec bulk packing line. For packing of above said product 60 cc HDPE bottle with 33 mm neck – DMF Grade ( SAP Grade : 2000996) and CR cap 33 mm with induction seal – DMF Grade (SAP Code- 2001305) were used.
Capsules were filled as defined count in BPR i.e. 90 capsules per bottle and one sachet desiccant was inserted in bottle with help of sachet desiccant inserter machine. Filled bottles were capped with the help of rotary capping machine. After capping, these filled & capped bottles were passed through induction sealing machine to seal the bottles as per defined parameters in BPR.
As per procedure during packing activity of batch no. 00818007 on line AQL was performed. While performing on line AQL, one partially sealed bottle was observed during inspection of shipper no.25 and one bottle was observed with sachet embedded in sealing in shipper number 26.
Similar incident of partially sealed bottle was observed previously (I/PR/18/086 dated: 08/May/2018) in product Lansoprazole Delayed Release Capsules USP 15 mg with the same bottle size and same caps (Material code: 2001305 Batch No. 0000061441) & vendor of packing material was Shriji polymer and Incident number I/PR/18/163 product Duloxetine delayed release capsules USP 60 mg batch number 00918007 Pack size: 30 capsules in bottle pack. On investigation, wrinkle observation to the sealing wad was observed and this leads to generation of partially sealed bottle.
Same caps were used for the product Duloxetine delayed release capsules USP 30 mg, similar observation was noted in this batch hence incident management is raised.
This report aims to identify root cause and propose actions for the observed partially sealed bottle and sachet embedded in sealing of sealed bottle in batch under investigation and to suggest suitable corrective and preventive action.
Actual photograph of partially sealed bottle:

Investigation related to packing process:
 Bulk packing activity of batch under investigation was initiated on countec bulk packing line on 28/Sep/2018.
 As per BPR procedure required pre-operational challenge tests for bottle unscrambler and air cleaner machine, Electronic multi-channel tablet and capsule counting machine , sachet desiccant inserter machine, Rotary capping machine, induction Cap sealer was performed and found satisfactory.
 Initial machine setting on bulk packing line was done as per below mentioned parameters;

Sr. No
Machine

 Standard. Parameter 

 Actual observation 

1 Bottle unscrambler Machine Distance between de-ionizing and bottle mouth = 4 mm
4 mm
2 Multi-channel tablet & capsule counting machine
No of counts per bottles : 90
90
3 Sachet Desiccant Inserter Machine One No. of PKT TRI Sorb 2 G 15 K/D- DMF ( 2 gm molecular sieve sachet) 01 No.
4 Rotary capping machine
Torque: to be recorded
24.3.0 to 24.4 lb
Checking of cap tightness OK/Not OK OK
5 Induction sealing machine
Distance between Cap and sealing head = 4 mm
4 mm
% Power (80 to 100 % ) 90 %
Conveyor speed ((30 bottles/Min) 30
Visual inspection for proper sealing OK/Not OK
OK

Evaluation: From the above table it is observed that all the parameters are well within the limit. Observed torque during capping in the range 24.3 to 24.4 lb and induction sealing parameter observed within defined range.
 Parameter comparison with earlier batches:

Sr. No Machine/
Process Standard. Parameter Actual observation for Batch No
Incident batch
(00818007) 00818006 00818005 00818004 00818003 00818002 00818001
1
Rotary capping machine/Capping Torque:
to be recorded 24.2 to 24.6 lb 24.3
to 26.4 lb 26.0 to 26.2
lb 26.0 to 26.2 lb 25.0 to 26.3 lb 26.0 to 26.4 lb 23.6 to 26.2 lb
Checking of cap tightness OK/Not OK OK OK OK OK OK OK OK
2 Induction sealing machine Distance between Cap and sealing head =4 mm 4 4 4 4 4 4 4
% Power (80 to 100 % ) 90 90 90 90 90 90 90
Conveyor Speed (30 bottles/Min) 30 30 30 30 30 30 30
Visual inspection for proper sealing OK/Not OK OK OK OK OK OK OK OK

Evaluation: Process parameters of previous batches are well within limit defined in BPR.
Observed torque during capping and induction sealing parameter in incident batch are comparable with earlier batches. For previous six batches (00818001 to 00818006) Torque observed in the range of 23.6 lb. to 26.4 lb.
In process checks recording:
Sr. No Machine/
Process Test Standard. Parameter Incident batch
(00818007)
1 Bottle unscrambler Machine Speed Record Observation 07 to 18 Bottles /min
Distance between de-ionising nozzle & bottle mouth 4mm OK
Visual Inspection for cleanliness OK OK
2 Multichannel counting Machine No. of units filled Outlet A
(Record the observation) 06 to 10 bottles /min
Outlet B (Record the observation) 09 bottles /min
Outlet C (Record the observation) 05 to 11 bottles /min
Outlet D (Record the observation) 09 to 10 bottles /min
3 Sachet Desiccant Inserter Machine Cuts/count 01 Cuts/count 01 Cuts/count
4
Rotary capping machine/Capping Torque:
to be recorded 24.2 to 24.6 lb
Checking of cap tightness OK/Not OK OK
5 Induction sealing machine Distance between Cap and sealing head =4 mm 4
% Power (80 to 100 % ) 90
Conveyor Speed (30 bottles/Min) 30
Visual inspection for proper sealing OK/Not OK OK
Evaluation: In process checks recorded during primary packing activity were found complying with specification. Though there was observation of partially sealed bottle during inspection, in process parameters were found satisfactory. Physical verification of partially sealed bottle was done and observed some wrinkle to the wad and hence available caps were physically inspected and observed similar wrinkle observation.

Another observation of sachet was observed embedded in sealing. Investigation with respect to filled bottle was done and following observations were noted.
 60 cc HDPE bottle with 33 mm neck – DMF Grade (SAP Grade: 2000996) and CR cap 33 mm with induction seal – DMF Grade (SAP Code- 2001305) were used.
 In one bottle, 90 capsules were filled along with one PKT TRI-SORB and then bottle was induction sealed.

Actual photograph : After sealing sachet found embedded in sealing wad and mouth of container After opening of bottle, capsule count found as defined 90 capsule and one sachet

 On physical verification of pack it was confirmed that total 90 capsules were filled and then sachet was filled. After sachet filling, bottle was capped and passed through induction sealing .During induction sealing upper portion of sachet was sealed in between induction sealing wad and mouth of bottle.
 In 60 cc bottle 90 capsules & one sachet inserted inside the bottle. There is manual intervention to forcefully push the sachet inside the bottle. Manually inserted sachet may regain its position during travel from sachet inserter to capping machine & cause the defect observed.
Investigation related to material:
Packing material issued and used for packing activity were sampled and tested by QC prior to release and only approved material were used for packing activity. Please find issued material details.
Material name Batch number A.R. No. Vendor name Required quantity
( Std. Qty/1.0 Lac) Issued quantity
HDPE Bottle 60 cc with 33 mm neck - DMF Grade 0000066279 10000251150 Shriji polymer 1074 1495
CR Cap 33 mm with induction seal - DMF Grade 0000066315 10000241551 Shriji polymer 1074 892
0000066537 10000253650 182
PKT TRI-SORB 2G (22X54) 15K/D - DMF REEL FORM 0000065155 10000245571 Clarient plastics and coating USA 1112 1074

 Observed wrinkle observation already taken with Vendor Shriji polymer:
Evaluation:
On visual inspection of cap, wrinkles to wad were observed. Observed wrinkle to the wad may be probable reason for generation of partially sealed bottle. This observation was taken with vendor to have suitable corrective and preventive action. Before use of cap, inspection of cap for the wrinkle observation was performed but may be this observed defective cap was missed during packing activity.
Observed sachet in sealing shown to all concerned to take proper care while manual insertion of sachet.
Investigation related to equipment and measurement
 Used equipment’s for batch packing are already in qualified status. Qualification details are mentioned below;

Sr. No. Equipment name Equipment ID Qualification Done on Qualification Due on
1 Rotary Capping machine PR301 15-Nov-17 Nov-2022
2 Induction sealing machine PR302 15-Nov-17 Nov-2022

 Preventive maintenance of equipment

Sr. No. Equipment name Equipment ID Preventive maintenance done on Due on
1 Rotary Capping machine PR301 Jul-18 Jan-19
2 Induction sealing machine PR302 Aug-18 Feb-19

 Preventive maintaince and qualification was carried out as defined schedule and no any abnormal observation was noted.
 Equipment parameters setting of rotary capping and induction sealing machine was done as defined in respective batch record.
4. Investigation related to personnel:
 Involved operator and packing /IPQA officer during packing are trained and competent to perform packing activity.
5. Investigation related to environment:
 Environmental condition maintained during packing activity were as defined in BPR.

Root Cause:
Observed partially sealed bottles were generated might be because of wrinkle observation to the induction sealing aluminium wad. This wrinkle observation already taken with vendor cap supplier ‘Shrii polymer’ and further Wad supplier ‘TEKNIPLEX’ and come know that it was might be because of improper coating wax during lamination process of wad and might be because of handling during punching.
Material failure. Wrinkle observation to induction sealing wad.
Observed sealed bottle with sachet embedded in sealing was and mouth of wad was because of improper insertion of sachet in bottle.

Corrective Action:

  1. 100 % inspection of sealed bottles was done. After 100 % inspection of bottle of batch under
    Investigation, no partially sealed bottle or sachet sealing in between sealing wad and mouth of bottle observed.
  2. Existing practice of checking of induction sealing wad of caps prior to loading of caps in hopper of rotary capping machine will be continued till receipt of cap with wad without wrinkle free observation.
    Risk Analysis:
    Observed partially sealed bottle observation may leads to exposure of product to external environment and it may leads to market complaint. All process parameters maintained for induction sealing machine were found as per BPR instructions. Partially sealed bottles defect was identified during inspection of packed product from shipper number 25 and sachet embedded in sealing of bottle observed in shipper number 26 as a part of AQL activity. This observation was noted in some of bottles those are having wrinkle to the induction sealing wad of cap. Wrinkle to the induction sealing wad leads to non-availability of uniform surface for sealing and this leads generation of partially sealed bottle. May be because of improper insertion of sachet, it was got embedded in sealing.
    Hence 100 % induction sealing checking of packed bottle of incident batch number 00818007 was done and partially sealed bottle or sachet embedded in sealing of bottle was not observed on 100 % inspection of packed shipper. Earlier batches of product Duloxetine DR Capsules USP 30 mg (90 count) checked and no similar observation noted.
    Caps were used in following commercial batches and AQL inspection report of the same was checked and observations were tabulated below;

Sr.No. SAP Batch number Used in Product name Product batch number Observation
1 0000064467 Duloxetine DR Capsules USP 30 mg(90’s) 00818004 No sealing defect observed
2 Duloxetine DR Capsules USP 30 mg(90’s) 00818005 No sealing defect observed
3 Duloxetine DR Capsules USP 30 mg(90’s) 00818006 No sealing defect observed
4 Duloxetine DR Capsules USP 30 mg(30’s) 00818006 No sealing defect observed
5 Duloxetine DR Capsules USP 60 mg(30’s) 00918004 No sealing defect observed
6 Duloxetine DR Capsules USP 60 mg(30’s) 00918005 No sealing defect observed
7 Duloxetine DR Capsules USP 60 mg(30’s) 00918006 No sealing defect observed
8 Duloxetine DR Capsules USP 60 mg(30’s) 00918007 Incident batch Under investigation
9 Duloxetine DR Capsules USP 60 mg(90’s) 00918007 No sealing defect observed
10 Duloxetine DR Capsules USP 60 mg(30’s) 00918009 No sealing defect observed
11 Lansoprazole DR Capsules,USP 15mg(30’s) A0IOR004 No sealing defect observed
12 Buspirone HCl Tablets, USP 15mg(100’s)
12018001 No sealing defect observed
13 0000066315 Buspirone HCl Tablets, USP 15mg(60’s) 12018003 No sealing defect observed
14 0000066165 Buspirone HCl Tablets,USP 15mg(100’s) 12018003 No sealing defect observed
15 0000066165 Buspirone HCl Tablets, USP 15mg(100’s) 12018004 No sealing defect observed
16 0000066165 Buspirone HCl Tablets,USP 15mg(100’s) 12018002 Partially sealed bottle observed- Separate incident No. I/PR/18/178 taken.
17 0000066315 Buspirone HCl Tablets,USP 15mg(60’s) 12018002
18 0000066165 Buspirone HCl Tablets,USP 15mg(100’s) 12018001 No sealing defect observed
19 0000065836 Buspirone HCl Tablets,USP 15mg(60’s) 12018001 No sealing defect observed
20 0000066165 Buspirone HCl Tablets,USP 15mg(60’s) 12018001 No sealing defect observed
21 0000066165 Duloxetine DR Capsules USP 60 mg(30’s) 00918009 No sealing defect observed
22 0000065836 Duloxetine DR Capsules USP 60 mg(30’s) 00918011 No sealing defect observed
23 0000065836 Duloxetine DR Capsules USP 60 mg(30’s) 00918010 No sealing defect observed
24 0000065836 Duloxetine DR Capsules USP 60 mg(30’s) 00918009 No sealing defect observed
25 0000064427 Duloxetine DR Capsules USP 60 mg(30’s) 00918009 No sealing defect observed
26 0000064427 Duloxetine DR Capsules USP 60 mg(30’s) 00918008 No sealing defect observed
27 0000065836 Duloxetine DR Capsules USP 60 mg(30’s) 00918008 No sealing defect observed
28 0000064427 Duloxetine DR Capsules USP 30 mg(30’s) 00818006 No sealing defect observed
29 0000051730 Duloxetine DR Capsules USP 60 mg(30’s) 00918004 No sealing defect observed
30 0000064427 Duloxetine DR Capsules USP 30 mg(30’s) 00818005 No sealing defect observed
31 0000064427 Duloxetine DR Capsules USP 30 mg(30’s) 00818004 No sealing defect observed
32 0000064427 Duloxetine DR Capsules USP 20 mg(60’s) 00718002 No sealing defect observed
33 0000064427 Duloxetine DR Capsules USP 20 mg(60’s) 00718001 No sealing defect observed
34 0000061295 Duloxetine DR Capsules USP 30 mg(30’s) 00818001 No sealing defect observed
35 0000061441 Duloxetine DR Capsules USP 30 mg(30’s) 00818002 No sealing defect observed
36 0000061295 Duloxetine DR Capsules USP 30 mg(30’s) 00818002 No sealing defect observed
37 0000061441 Duloxetine DR Capsules USP 30 mg(90’s) 00818001 No sealing defect observed
38 0000061441 Duloxetine DR Capsules USP 30 mg(90’s) 00818002 No sealing defect observed
39 0000061441 Duloxetine DR Capsules USP 30 mg(90’s) 00818003 No sealing defect observed
40 0000061441 Duloxetine DR Capsules USP 30 mg(30’s) 00818003 No sealing defect observed
41 0000063729 Duloxetine DR Capsules USP 30 mg(30’s) 00818001 No sealing defect observed
42 0000063729 Duloxetine DR Capsules USP 30 mg(30’s) 00818003 No sealing defect observed
43 0000064298 Duloxetine DR Capsules USP 60 mg(30’s) 00918001 No sealing defect observed
44 0000064298 Duloxetine DR Capsules USP 60 mg(30’s) 00918002 No sealing defect observed
45 0000064298 Duloxetine DR Capsules USP 60 mg(30’s) 00918003 No sealing defect observed
46 0000064427 Duloxetine DR Capsules USP 60 mg(30’s) 00918003 No sealing defect observed
47 0000063729 Duloxetine DR Capsules USP 60 mg(30’s) 00918001 No sealing defect observed
48 0000064427 Fluoxetine Tablets 60 mg 30’s Count 12218004 No sealing defect observed
49 0000064298 Fluoxetine Tablets 60 mg 30’s Count 12218004 No sealing defect observed
50 0000063729 Fluoxetine Tablets 60 mg 30’s Count 12218004 No sealing defect observed
51 0000061441 Fluoxetine Tablets 60 mg 30’s Count 12218004 No sealing defect observed
52 0000064427 Fluoxetine Tablets 60 mg 30’s Count 12218005 No sealing defect observed
53 0000064427 Fluoxetine Tablets 60 mg 30’s Count 12218006 No sealing defect observed
54 0000066315 Buspirone HCl Tablets,USP 5mg(100’s) 11718004 No sealing defect observed
55 0000066315 Buspirone HCl Tablets,USP 5mg(100’s) 11718005 No sealing defect observed
56 0000066315 Buspirone HCl Tablets,USP 5mg(100’s) 11718006 No sealing defect observed
57 0000066315 Duloxetine DR Capsules USP 30 mg(30’s) 00818007 No sealing defect observed
58 0000066315 Duloxetine DR Capsules USP 30 mg(30’s) 00818009 No sealing defect observed
59 0000066315 Duloxetine DR Capsules USP 30 mg(90’s) 00818007 Batch under investigation.
60 0000066537 Buspirone HCl Tablets,USP 10mg(100’s) 11918004 No sealing defect observed
61 0000066537 Buspirone HCl Tablets,USP 10mg(100’s) 11918005 No sealing defect observed
62 0000066537 Duloxetine DR Capsules USP 30 mg(30’s) 00818008 No sealing defect observed
63 0000066537 Duloxetine DR Capsules USP 30 mg(90’s) 00818007 Batch under investigation.
64 0000066537 Duloxetine DR Capsules USP 30 mg(30’s) 00818007 No sealing defect observed
65 0000066537 Duloxetine DR Capsules USP 30 mg(30’s) 00818012 No sealing defect observed
66 0000066537 Duloxetine DR Capsules USP 30 mg(30’s) 00818009 No sealing defect observed

Earlier packed batches data of Duloxetine DR capsules USP 30 mg (90 count)
Sr.No. Used in Product name Product batch number Observation
1 Duloxetine DR Capsules USP 30 mg(90’s) 00818001 No sachet embedded in sealing defect observed
2 Duloxetine DR Capsules USP 30 mg(90’s) 00818002 No sachet embedded in sealing defect observed
3 Duloxetine DR Capsules USP 30 mg(90’s) 00818003 No sachet embedded in sealing defect observed
4 Duloxetine DR Capsules USP 30 mg(90’s) 00818004 No sachet embedded in sealing defect observed
5 Duloxetine DR Capsules USP 30 mg(90’s) 00818005 No sachet embedded in sealing defect observed
6 Duloxetine DR Capsules USP 30 mg(90’s) 00818006 No sachet embedded in sealing defect observed

Leak test of sealed bottle was verified during online activity and found satisfactory. Batches wherein CR cap 33 mm were used , no defect observed during AQL inspection and defect observed batches were inspected 100 %, hence no risk identified with respect to pack integrity.

Preventive Action:

  1. Observed wrinkle to the induction sealing wad of caps was taken with vendor Shriji polymer and asked to provide investigation and CAPA. As action mentioned by wad supplier, Tekniflex and as part of corrective action wad supplier installed new coating cylinder with improved coating pattern from March 18 and increase visual inspection of liner during lamination and slitting process.
  2. To avoid manual insertion error and to create awareness, retraining to be provided to concerned person.

Prepared By:


(YOGESH NARKHEDE) #28

Annexure - III
Investigation Report Format
Purpose:
Purpose of this incident investigation report is to identify the probable root cause for Use of Magnesium stearate of code 1500902 instead of code 1500105 and to suggest the suitable corrective and preventive action.
Investigation:

  1. As per Deviation No. D/PR/18/011 SAP Code - 1500429 of Magnesium stearate of Valtris to be write manually in BMR of Panfor SR 500 & Panfor SR 1000 instead of 1500105.
  2. But the Item code 1500902 was written manually in the attached list of batches.
  3. On further interview with involved Person Mr. Bhavesh Kolam ( Production) and Mr. Vishal Bhosale, it was observed that instructions were received from senior persons for writing the Material code 1500902 by cutting the item code 1500105.
  4. It was oversightly missed from all the concerned persons. Also observed that Printed material code was cut by production person and written the code to be dispensed.
    Root Cause:
    Personnel Failure.
  5. Oversight in reading of approved deviation Copy of deviation.
    Corrective Action:
  6. Printed matter in BMR to be cut by QA personnel only.
  7. Instructed concerned persons to follow the BMR written instructions.
    Risk Analysis:
    Both the material code have the same specification, hence no risk to the product quality.
    Preventive Action:
  8. Hence fourth Code to code transfer to be done in case of same specification materials.
    Prepared By: Reviewed By

(YOGESH NARKHEDE) #29

Annexure III
Investigation Report Format I/PR/18/170
Purpose:
Purpose of this annexure is the investigation of in process checks entry made on page number 10 F of 17.
Scope:
The Scope of this annexure is applicable to Telsite 20 mg , B.No.0718003
B.Size:220000 Tablets.
Mfg.date-Aug.2018
Expiry date: Jul.2021
Marketed by :Sanofi India Ltd.
Background
During review BMR of Telsite 40 mg, Batch No.: 0718004 it was observed that page number 10 P & 10Q of 17 was printed on 31/Aug/2018 02:01:34 PM (i.e. 14:01:34 Hrs.) and recording on the same page was made from 12:15 to 13:35 hence incident I/PR/18/170 was initiated to investigate the failure and provide CAPA, similar failure was observed in the Telsite 20 mg , B.No.0718003.
Investigation:
During review of BMR of Telsite 20 mg , B.No.0718003 it was observed that page number 10 F of 17 was printed on 30/Aug/2018 at 08:05:41 AM, and entries of inprocess checks was made for the time 07:42 (30/Aug/2018).
This batch was planned for compression on 29/Aug/2018 in SP09 area, during compression concern person made last entry of in process checks up to 07:38 (30/Aug/2018) on page number 10 E of 17, after that concern person initiated additional page requisition, got approval for the same and printed the page on 08:05:41 AM on 30/Aug/2018, after receiving the page concern person handed over page to respective technician, prior to that batch was completed and concern technician noted time of batch stop as 07:42 (30/Aug/2018) on the page number 11 of 17. Same time he Tran scripted to page number 10 F of 17.
Root Cause:
Root cause of incident is transcription error.
Corrective Action:
Time noted on page number 10 F of 17 was verified against the batch completion time recorded on page number 11 of 17.
SOP Ref. No.: CQ/003 Page 2 of 2
Format No.: CQ/003/F-03
Risk Analysis:
As recorded time verified there is no impact with respect to quality of product and data recorded.
Preventive Action:
GDP training shall be provided to concern person.
Prepared By: Reviewed By: Approved


(YOGESH NARKHEDE) #30

Annexure III
Investigation Report Format
Purpose:
Purpose of this annexure is to investigate the less yield at compression stage of Tonact FN (Atorvastatin 10 mg and Fenofibrate 160 mg tablets ) Batch no. A04931805 & A04931806
Scope:
The Scope of this annexure is applicable to Tonact FN (Atorvastatin 10 mg and Fenofibrate 160 mg tablets ) Batch no. A04931805 & A04931806
Background
At compression stage during reconcillation it was observed that the % yield of batch A04931805 was 77.59 % and batch A04931806 was 85.13 % against the standards yield limit NLT 88 % and
Investigation:
Following are the reconciliation details.
Tonact FN-A04931805
1
Standard theoretical batch size 157.25 kg ≈ 170000 tablets
2
Actual Quantity transferred for next stage: (Kg) =115.620≈124846 Nos
3
Sample Quantity (a+b+c)
Kg
No
a) In process Sample
1.575
900+800
b) QC Sample
0.125
135
c) Other sample during compression

Total (a+b+c)
1.7
1835
4
Handling Waste (d+e+f) = 33.50 kg
d) Atorvastatin granules left over in Kg: 0.400 kg
e) Fenofibrate granules left over in Kg: 20.20 kg°
f) Reject (i+ii+iii)
Sr. no.
Qty of Tablet rejected
Kg
No.
i)
During compression
2.9*+1.1**
3131+1187
ii)
During Inspection

iii)
Other rejection
8.900****

5
Total Rejects = Step 4 + a = 35.075 kg
6
% Standard Yield {( Step 2+Step 3) / Step 1 X100 } = 77.59 %
Range for % yield = NLT88% w/w
7
% Reconciliation {(Step 2 + Step 3 + Step 4) / Step 1 X 100} = 99.74 %
*2.900 kg rejection during initial setting
**1.100 kg rejection during compression
****8.900 kg Layer I dust i.e. Atorvastatin
° Fenofibrate granules left over 20.200 kg
SOP Ref. No.: CQ/003 Page 2 of 2
Format No.: CQ/003/F-03
Tonact FN-A04931806
1
Standard theoretical batch size 157.25 kg ≈ 170000 tablets
2
Actual Quantity transferred for next stage: (Kg) =131.830≈142411 Nos
3
Sample Quantity (a+b+c)
Kg
No
a) In process Sample
1.405
720+800
b) QC Sample
0.125
135
c) Other sample during compression

Total (a+b+c)
1.53
1655
4
Handling Waste (d+e+f) = 22.100 kg
d) Atorvastatin granules left over in Kg: 0.200kg
e) Fenofibrate granules left over in Kg: 8.50 kg°°
f) Reject (i+ii+iii)
Sr. no.
Qty of Tablet rejected
Kg
No.
i)
During compression
1.900*+2.100**
4321
ii)
During Inspection

iii)
Other rejection
5.400***+4.000°

5
Total Rejects = Step 4 + a = 23.505 kg
6
% Standard Yield {( Step 2+Step 3) / Step 1 X100 } = 85.13 %
Range for % yield = NLT88% w/w
7
% Reconciliation {(Step 2 + Step 3 + Step 4) / Step 1 X 100} = 99.24 %
*1.900kg rejection during initial setting
**2.100 kg in process rejection during compression
***5.400 kg layer I dust i.e. atorvastatin
°4.000 kg layer II dust i.e. fenofibrate
°°8.500 kg Finofibrate granules left over .
Root Cause:
Root cause for less yield is generation of more dust atorvastatin and fenofibrate granules .
Risk Analysis:
Since yield of the batch is less than the specified limit there is no impact on the product quality is anticipated.
Preventive Action:
Further batches shall be monitored for yield .
Prepared By: Reviewed By: Approved By:


(YOGESH NARKHEDE) #31

Annexure - III
Investigation Report for I/PR/18/163
Purpose:
Purpose of this investigation is to identify the root cause and to determine appropriate corrective and preventive actions for observed one partially sealed bottle during inspection of shipper no. 21 during packing of product Duloxetine Delayed release capsules USP 60 mg.

Scope:
This is applicable to product Duloxetine Delayed Release capsules USP 60 mg.
Batch number: 00918007
Pack size: 30 capsules in bottle pack
Mfg. date: Jun.2018
Exp. date: May.2020
Batch size: 387.45 kg ~ 1025000 capsules

Background:
Product Duloxetine Delayed Release capsules USP 60 mg is manufactured and packed for US Market at Inventia Healthcare Limited. Required quantities of packing materials were issued as per batch requirement.
Bulk packing activity was initiated on countec bulk packing line. For packing of above said product 60 cc HDPE bottle with 33 mm neck – DMF Grade ( SAP Grade : 2000996) and CR cap 33 mm with induction seal – DMF Grade (SAP Code- 2001305) were used.
Capsules were filled as defined count in BPR i.e. 30 capsules per bottle and one sachet desiccant was inserted in bottle with help of sachet desiccant inserter machine. Filled bottles were capped with the help of rotary capping machine. After capping, these filled & capped bottles were passed through induction sealing machine to seal the bottles as per defined parameters in BPR.
As per procedure during packing activity of batch no. 00918007 on line AQL was performed. While performing on line AQL, one partially sealed bottle was observed during inspection of shipper no.21.
Similar incident was observed previously (I/PR/18/086 dated: 08/May/2018) in product Lansoprazole Delayed Release Capsules USP 15 mg with the same bottle size and same caps (Material code : 2001305 Batch No. 0000061441) & vendor of packing material was Shriji polymer. Same caps were used for the product Duloxetine delayed release capsules USP 60 mg, similar observation was noted in this batch hence incident management is raised.
This report aims to identify root cause and propose actions for the observed partially sealed bottle in batch under investigation and to suggest suitable corrective and preventive action.

Investigation:
Ishikawa (Fish bone diagram) was drawn come to investigation

Training Qualification

Machine setting Preventive /Breakdown
Maintenance
Lack of knowledge
Temperature /RH Capping machine setting parameter
In area
Induction sealing setting parameter

 Wad thickness                  Specification 
                                      of wad                                        % Power, Distance  and speed         Induction sealing 
                                                                                                                                        Parameter 

Cap

      Physical                                                                                           Capping/Closing Torque
   Condition 
    Of wad                                                        Bottles

Wrinkle observation to wad

Actual photograph of partially sealed bottle:

Investigation related to packing process:
 Bulk packing activity of batch under investigation was initiated on countec bulk packing line on 19/Aug/2018.
 As per BPR procedure required pre-operational challenge tests for bottle unscrambler and air cleaner machine, Electronic multi-channel tablet and capsule counting machine , sachet desiccant inserter machine, Rotary capping machine, induction Cap sealer was performed and found satisfactory.
 Initial machine setting on bulk packing line was done as per below mentioned parameters;

Sr. No
Machine

 Standard. Parameter 

 Actual observation 

1 Bottle unscrambler Machine Distance between de-ionizing and bottle mouth = 4 mm
4 mm
2 Multi-channel tablet & capsule counting machine
No of counts per bottles : 30
30
3 Sachet Desiccant Inserter Machine One No. of PKT TRI Sorb 2 G 15 K/D- DMF ( 2 gm molecular sieve sachet) 01 No.
4 Rotary capping machine
Torque: to be recorded
26.0 to 26.8 lb
Checking of cap tightness OK/Not OK OK
5 Induction sealing machine
Distance between Cap and sealing head = 4 mm
4 mm
% Power (80 to 100 % ) 90 %
Conveyor speed ((30 bottles/Min) 30
Visual inspection for proper sealing OK/Not OK
OK

Evaluation: From the above table it is observed that all the parameters are well within the limit. Observed torque during capping in the range 26 to 26.8 lb and induction sealing parameter observed within defined range.
 Parameter comparison with earlier batches:

Sr. No Machine/
Process Standard. Parameter Actual observation for Batch No
Incident batch
(00918007) 00918006 00918005 00918004 00918003 00918002 00918001
1
Rotary capping machine/Capping Torque:
to be recorded 26.0 to 26.8 lb 26.0 to 26.8 lb 26.0 to 26.8 lb 26.0 to 26.8 lb 26.0 to 26.5 lb 25.8 to 26.4 lb 26.1 to 26.7 lb
Checking of cap tightness OK/Not OK OK OK OK OK OK OK OK
2 Induction sealing machine Distance between Cap and sealing head =4 mm 4 4 4 4 4 4 4
% Power (80 to 100 % ) 90 90 90 90 90 90 60,90 & 100
Conveyor Speed (30 bottles/Min) 30 30 30 30 30 30 30
Visual inspection for proper sealing OK/Not OK OK OK OK OK OK OK OK

Evaluation: Process parameters of previous batches are well within limit defined in BPR.
Observed torque during capping and induction sealing parameter in incident batch are comparable with earlier batches. For previous six batches (00918002 to 00918006) Torque observed in the range of 25.8 lb to 26.8 lb. Torque range is not defined in the BPR.
 In process checks recording:
Sr. No Machine/
Process Test Standard. Parameter Incident batch
(00918007)
1 Bottle unscrambler Machine Speed Record Observation 21 to 60 Bottles /min
Distance between de-ionising nozzle & bottle mouth 4mm OK
Visual Inspection for cleanliness OK OK
2 Multichannel counting Machine No. of units filled Outlet A
(30 Bottles /min) 10 – 18 bottles /min
Outlet B (30 Bottles /min) 11 – 19 bottles /min
Outlet C (30 Bottles /min) 11 – 18 bottles /min
Outlet D (30 Bottles /min) 10 – 19 bottles /min
3 Sachet Desiccant Inserter Machine Cuts/count 01 Cuts/count 01 Cuts/count
4
Rotary capping machine/Capping Torque:
to be recorded 26.0 to 26.8 lb
Checking of cap tightness OK/Not OK OK
5 Induction sealing machine Distance between Cap and sealing head =4 mm 4
% Power (80 to 100 % ) 90
Conveyor Speed (30 bottles/Min) 30
Visual inspection for proper sealing OK/Not OK OK

Evaluation: In process checks recorded during primary packing activity were found complying with specification. Though there was observation of partially sealed bottle during inspection, in process parameters were found satisfactory. Physical verification of partially sealed bottle was done and observed some wrinkle to the wad and hence available caps were physically inspected and observed similar wrinkle observation. Hence investigation was extended to material.

Investigation related to material:
Packing material issued and used for packing activity were sampled and tested by QC prior to release and only approved material were used for packing activity. Please find issued material details.
Material name Batch number A.R. No. Vendor name Required quantity
( Std. Qty/1.0 Lac) Issued quantity
HDPE Bottle 60 cc with 33 mm neck - DMF Grade 0000065613 10000248528 Shriji polymer 24961 25500
CR Cap 33 mm with induction seal - DMF Grade 0000064467 10000241551 Shriji polymer 24961 25043
PKT TRI-SORB 2G (22X54) 15K/D - DMF REEL FORM 0000065155 10000245571 Clarient plastics and coating USA 24961 27710

 QC analytical results of used cap was checked and all tests for Caps observed complying with specification except Total wad thickness. For total wad thickness observations were noted only for information, limit not defined in specification. Observations for total wad width were as follows.

Sr. No. AR No. Observation for total wad thickness
Specification- 0.65 mm ± 0.02 mm [0.63 to
0.67 mm][For Information
only]
1 10000241551 0.583 mm ( used in Incident Batch)
2 10000240620 0.588 mm
3 10000241338 0.590 mm
4 10000249933 0.587 mm
5 10000252431 0.589 mm
6 10000222894 0585 mm

 Supplier total wad thickness. : 0.589 ± 10 % ( 0.530 mm to 0.648 mm )
 Samples from unused caps of this lot number were verified and on physical verification of cap wrinkles were observed.

                   Photograph of Cap with wrinkle observation

 Observed wrinkle observation was taken with Vendor Shriji polymer:
Evaluation:
Observed wad thickness was lower than the defined specification however it was only for information. On visual inspection of cap, wrinkles to wad were observed. Observed wrinkle to the wad may be probable reason for generation of partially sealed bottle. This observation was taken with vendor to have suitable corrective and preventive action within 15 working days.
Investigation related to equipment and measurement
 Used equipment’s for batch packing are already in qualified status. Qualification details are mentioned below;

Sr. No. Equipment name Equipment ID Qualification Done on Qualification Due on
1 Rotary Capping machine PR301 15-Nov-17 Nov-2022
2 Induction sealing machine PR302 15-Nov-17 Nov-2022

 Preventive maintenance of equipment

Sr. No. Equipment name Equipment ID Preventive maintenance done on Due on
1 Rotary Capping machine PR301 Jul-18 Jan-19
2 Induction sealing machine PR302 Aug-18 Feb-19

 Preventive maintaince and qualification was carried out as defined schedule and no any abnormal observation was noted.
 Equipment parameters setting of rotary capping and induction sealing machine was done as defined in respective batch record.
4. Investigation related to personnel:
 Involved operator and packing /IPQA officer during packing are trained and competent to perform packing activity.
5. Investigation related to environment:
 Environmental condition maintained during packing activity were as defined in BPR.

Root Cause:
Observed partially sealed bottles were generated might be because of wrinkle observation to the induction sealing aluminium wad.
Material failure. Wrinkle observation to induction sealing wad.

Corrective Action:

  1. 100 % inspection of sealed bottles was done. After 100 % inspection of bottle of batch under
    Investigation, total 34 partially sealed bottles were observed.
  2. Existing induction sealing wad of caps to be checked prior to loading of caps in hopper of rotary capping machine and activity to be recorded in BPR.
  3. Torque range to be defined in BPR for rotary Capper machine.
  4. Total Wad thickness range need to be defined in specification.
    Risk Analysis:
    Observed partially sealed bottle observation may leads to exposure of product to external environment and it may leads to market complaint. All process parameters maintained for induction sealing machine were found as per BPR instructions. Partially sealed bottles defect was identified during inspection of packed product from shipper number 21 as a part of AQL activity. This observation was noted in some of bottles those are having wrinkle to the induction sealing wad of cap. Wrinkle to the induction sealing wad leads to non-availability of uniform surface for sealing and this leads generation of Partially sealed bottle.
    Hence 100 % induction sealing checking of packed bottle of incident batch number 00918007 was done and ensure no partially sealed bottle packing in packed shipper.
    Caps were used in following commercial batches and AQL inspection report of the same was checked and observations were tabulated below;

Sr.No. SAP Batch number Used in Product name Product batch number Observation
1 0000064467 Duloxetine DR Capsules USP 30 mg(90’s) 00818004 No sealing defect observed
2 Duloxetine DR Capsules USP 30 mg(90’s) 00818005 No sealing defect observed
3 Duloxetine DR Capsules USP 30 mg(90’s) 00818006 No sealing defect observed
4 Duloxetine DR Capsules USP 30 mg(30’s) 00818006 No sealing defect observed
5 Duloxetine DR Capsules USP 60 mg(30’s) 00918004 No sealing defect observed
6 Duloxetine DR Capsules USP 60 mg(30’s) 00918005 No sealing defect observed
7 Duloxetine DR Capsules USP 60 mg(30’s) 00918006 No sealing defect observed
8 Duloxetine DR Capsules USP 60 mg(30’s) 00918007 Incident batch Under investigation
9 Duloxetine DR Capsules USP 60 mg(90’s) 00918007 No sealing defect observed
10 Duloxetine DR Capsules USP 60 mg(30’s) 00918009 No sealing defect observed
11 Lansoprazole DR Capsules,USP 15mg(30’s) A0IOR004 No sealing defect observed
12 Buspirone HCl Tablets, USP 15mg(100’s)
12018001 No sealing defect observed
13 0000066315 Buspirone HCl Tablets, USP 15mg(60’s) 12018003 No sealing defect observed
14 0000066165 Buspirone HCl Tablets,USP 15mg(100’s) 12018003 No sealing defect observed
15 0000066165 Buspirone HCl Tablets, USP 15mg(100’s) 12018004 No sealing defect observed
16 0000066165 Buspirone HCl Tablets,USP 15mg(100’s) 12018002 Partially sealed bottle observed- Separate incident No. I/PR/18/178 taken.
17 0000066315 Buspirone HCl Tablets,USP 15mg(60’s) 12018002
18 0000066165 Buspirone HCl Tablets,USP 15mg(100’s) 12018001 No sealing defect observed
19 0000065836 Buspirone HCl Tablets,USP 15mg(60’s) 12018001 No sealing defect observed
20 0000066165 Buspirone HCl Tablets,USP 15mg(60’s) 12018001 No sealing defect observed
21 0000066165 Duloxetine DR Capsules USP 60 mg(30’s) 00918009 No sealing defect observed
22 0000065836 Duloxetine DR Capsules USP 60 mg(30’s) 00918011 No sealing defect observed
23 0000065836 Duloxetine DR Capsules USP 60 mg(30’s) 00918010 No sealing defect observed
24 0000065836 Duloxetine DR Capsules USP 60 mg(30’s) 00918009 No sealing defect observed
25 0000064427 Duloxetine DR Capsules USP 60 mg(30’s) 00918009 No sealing defect observed
26 0000064427 Duloxetine DR Capsules USP 60 mg(30’s) 00918008 No sealing defect observed
27 0000065836 Duloxetine DR Capsules USP 60 mg(30’s) 00918008 No sealing defect observed
28 0000064427 Duloxetine DR Capsules USP 30 mg(30’s) 00818006 No sealing defect observed
29 0000051730 Duloxetine DR Capsules USP 60 mg(30’s) 00918004 No sealing defect observed
30 0000064427 Duloxetine DR Capsules USP 30 mg(30’s) 00818006 No sealing defect observed
31 0000064427 Duloxetine DR Capsules USP 30 mg(30’s) 00818005 No sealing defect observed
32 0000064427 Duloxetine DR Capsules USP 30 mg(30’s) 00818004 No sealing defect observed
33 0000064427 Duloxetine DR Capsules USP 20 mg(60’s) 00718002 No sealing defect observed
34 0000064427 Duloxetine DR Capsules USP 20 mg(60’s) 00718001 No sealing defect observed
35 0000061295 Duloxetine DR Capsules USP 30 mg(30’s) 00818001 No sealing defect observed
36 0000061441 Duloxetine DR Capsules USP 30 mg(30’s) 00818002 No sealing defect observed
37 0000061295 Duloxetine DR Capsules USP 30 mg(30’s) 00818002 No sealing defect observed
38 0000061441 Duloxetine DR Capsules USP 30 mg(90’s) 00818001 No sealing defect observed
39 0000061441 Duloxetine DR Capsules USP 30 mg(90’s) 00818002 No sealing defect observed
40 0000061441 Duloxetine DR Capsules USP 30 mg(90’s) 00818003 No sealing defect observed
41 0000061441 Duloxetine DR Capsules USP 30 mg(30’s) 00818003 No sealing defect observed
42 0000063729 Duloxetine DR Capsules USP 30 mg(30’s) 00818001 No sealing defect observed
43 0000063729 Duloxetine DR Capsules USP 30 mg(30’s) 00818003 No sealing defect observed
44 0000064298 Duloxetine DR Capsules USP 60 mg(30’s) 00918001 No sealing defect observed
45 0000064298 Duloxetine DR Capsules USP 60 mg(30’s) 00918002 No sealing defect observed
46 0000064298 Duloxetine DR Capsules USP 60 mg(30’s) 00918003 No sealing defect observed
47 0000064427 Duloxetine DR Capsules USP 60 mg(30’s) 00918003 No sealing defect observed
48 0000063729 Duloxetine DR Capsules USP 60 mg(30’s) 00918001 No sealing defect observed
49 0000064427 Duloxetine DR Capsules USP 60 mg(30’s) 00918003 No sealing defect observed
50 0000064427 Fluoxetine Tablets 60 mg 30’s Count 12218004 No sealing defect observed
51 0000064298 Fluoxetine Tablets 60 mg 30’s Count 12218004 No sealing defect observed
52 0000063729 Fluoxetine Tablets 60 mg 30’s Count 12218004 No sealing defect observed
53 0000061441 Fluoxetine Tablets 60 mg 30’s Count 12218004 No sealing defect observed
54 0000064427 Fluoxetine Tablets 60 mg 30’s Count 12218005 No sealing defect observed
55 0000064427 Fluoxetine Tablets 60 mg 30’s Count 12218006 No sealing defect observed

Leak test of sealed bottle was verified during online activity and found satisfactory. Batches wherein CR cap 33 mm were used , no defect observed during AQL inspection and defect observed batches were inspected 100 %, hence no risk identified with respect to pack integrity.

Preventive Action:

  1. Observed wrinkle to the induction sealing wad of caps taken with vendor Shriji polymer and asked to provide investigation and CAPA within 15 working days. Based on vendor investigation and CAPA further action plan will be decided.
    2. All the products having CR Cap 33 mm with induction seal to be identified and torque range to be defined in respective BPR based on validation batches data for rotary Capper machine.

Prepared By: Reviewed By: Approved By:


(YOGESH NARKHEDE) #32


(YOGESH NARKHEDE) #33

Attachment to Incident Investigation I/PR/18/162
Purpose:
Purpose of this annexure is to investigate the cause of compression of Panfor SR 500 B.no.PAF01421, PAF01422,PAF01423,PAF01424 at 18 RPM on 51 station Giga press tablet compression machine instead of 25-30 RPM.
Scope:
The Scope of this annexure is applicable to
Panfor SR 500 B.no. PAF01421, PAF01422,PAF01423,PAF01424
Planned B.Size:1030000Tablets.
Mfg. Date-Oct .2018
Exp. Date Sep.2021
Marketed by: Mega life sciences
Background:
Panfor SR 500 is single layer product, with composition of Metformin HCL SR granules 59.88% w/w. Compression of Panfor SR 500 B.no. PAF01421, PAF01422,PAF01423,PAF01424 done on 51 station Giga press compression machine. In these all batchs to get the hardness within the specification compression machine speed were reduced.
Investigation:

  1. Panfor SR 500 B.no.PAF01421 is single layer product, with composition of Metformin HCL SR granules 59.88% w/w. The batch was planned for compression on tablet compression machine 51 station giga press.During initial setting machine RPM was kept at 25 RPM, while at this RPM concern person was found that specified hardness is not achieved for some tablet i.e for LHS (9.70 to 11.30kp ) and RHS ( 9.60 to 11.50kp ) against the specified limit mention in BMR ( NLT 10kp ).Hence speed was reduced to 18 RPM, at this RPM i.e. 18 RPM all parameters are found well within the specified limit mentioned in BMR.
    0.200gm sample of granules was withdrawn for physical property test.Rejection generated during initial setting ( 2.40kg ) was destroyed.
  2. Panfor SR 500 B.no.PAF01422 is single layer product, with composition of Metformin HCL SR granules 59.88% w/w. The batch was planned for compression on tablet compression machine 51 station giga press.During initial setting machine RPM was kept at 25 RPM, while at this RPM concern person was found that specified hardness is not achieved for some tablet i.e for LHS (9.70 to 11.20kp ) and RHS ( 9.80 to 11.80kp ) against the specified limit mention in BMR ( NLT 10kp ).Hence speed was reduced to 18 RPM, at this RPM i.e. 18 RPM all parameters are found well within the specified limit mentioned in BMR. 0.200gm sample of granules was withdrawn for physical property test.Rejection generated during initial setting (7.90kg ) was destroyed.
  3. Panfor SR 500 B.no.PAF01423 is single layer product, with composition of Metformin HCL SR granules 59.88% w/w. The batch was planned for compression on tablet
    SOP Ref. No. : CQ/003 Page 2 of 4
    Format No.: CQ/003/F-03
    compression machine 51 station giga press.During initial setting machine RPM was kept at 25 RPM, while at this RPM concern person was found that specified hardness is not achieved for some tablet i.e for LHS (9.70 to 12.00kp ) and RHS ( 9.80 to 13.10kp ) against the specified limit mention in BMR ( NLT 10kp ).Hence speed was reduced to 18 RPM, at this RPM i.e. 18 RPM all parameters are found well within the specified limit mentioned in BMR. 0.200gm sample of granules was withdrawn for physical property test.Rejection generated during initial setting (0.97 kg ) was destroyed.
  4. Panfor SR 500 B.no.PAF01424 is single layer product, with composition of Metformin HCL SR granules 59.88% w/w. The batch was planned for compression on tablet compression machine 51 station giga press.During initial setting machine RPM was kept at 25 RPM, while at this RPM concern person was found that specified hardness is not achieved for some tablet i.e for LHS (13.4 to 14.40kp ) and RHS ( 9.80 to 13.20kp ) against the specified limit mention in BMR ( NLT 10kp ).Hence speed was reduced to 18 RPM, at this RPM i.e. 18 RPM all parameters are found well within the specified limit mentioned in BMR. 0.200gm sample of granules was withdrawn for physical property test.Rejection generated during initial setting (3.40 kg ) was destroyed.
    Investigation related to process: Granulation
    Sr.no.
    Panfor SR 500 (Metfromin Hydrochloride SR granules 59.88% w/w).
    B.no.PAF01421
    1
    Binder Solution
    Granulation Time
    Ammpere Reading
    Co mill speed
    Lot 01
    Lot02
    Lot 01
    Lot02
    Lot 01
    Lot02
    Lot 01
    Lot02
    120.90Kg
    120.90kg
    28mins
    28mins
    49.8Amp
    54.2Amp
    550RPM
    550RPM
    2
    Panfor SR 500 (Metfromin Hydrocloride SR granules 59.88% w/w). B.no.PAF01422
    Binder Solution
    Granulation Time
    Ammpere Reading
    Co mill speed
    Lot 01
    Lot02
    Lot 01
    Lot02
    Lot 01
    Lot02
    Lot 01
    Lot02
    120.90kg
    120.90kg
    28mins
    28mins
    54.60amp
    54.20amp
    550RPM
    550 RPM
    3
    Panfor SR 500 (Metfromin Hydrochloride SR granules 59.88% w/w).
    B.no.PAF01423
    Binder Solution
    Granulation Time
    Ammpere Reading
    Co mill speed
    Lot 01
    Lot02
    Lot 01
    Lot02
    Lot 01
    Lot02
    Lot 01
    Lot02
    120.88KG
    120.88KG
    28mins
    28mins
    55.2amp
    57.7amp
    550RPM
    550RPM
    4
    Panfor SR 500 (Metfromin Hydrochloride SR granules 59.88% w/w).
    B.no.PAF01424
    Binder Solution
    Granulation Time
    Ammper Reading
    Co mill speed
    Lot 01
    Lot02
    Lot 01
    Lot02
    Lot 01
    Lot02
    Lot 01
    Lot02
    120.90KG
    120.90KG
    28MINS
    28mins
    54.7amp
    56.2amp
    500rpm
    500rpm
    = Standard limit for Granulation time 19 to 30 Mins.
    = Standard limit for Ammper limit 40 to 60 Amp.
    =Standard limit for comill speed 500 to 550 Amp.
    SOP Ref. No. : CQ/003 Page 3 of 4
    Format No.: CQ/003/F-03
    Sr.no.
    1
    LOD
    Panfor SR 500 (Metfromin Hydrochloride SR granules 59.88% w/w). B.no.PAF01421
    Lot 01
    Lot02
    Lubrication granules
    Limit
    3.63%
    4.13%
    4.12
    3.5 – 4.5%
    2
    Panfor SR 500 (Metfromin Hydrochloride SR granules 59.88% w/w). B.no.PAF01422
    Lot 01
    Lot02
    Lubrication granules
    Limit
    4.19%
    3.76%
    4.03%
    3.5 – 4.5%
    3
    Panfor SR 500 (Metfromin Hydrochloride SR granules 59.88% w/w). B.no.PAF01423
    Lot 01
    Lot02
    Lubrication granules
    Limit
    3.65%
    3.92%
    4.38%
    3.5 – 4.5%
    4
    Panfor SR 500 (Metfromin Hydrochloride SR granules 59.88% w/w). B.no.PAF01424
    Lot 01
    Lot02
    Lubrication granules
    Limit
    3.86%
    4.02%
    4.15%
    3.5 – 4.5%
    Evaluation :
    On review of granulation parameter of batches under investigation it was observed that all granulation parameter are complying.It may be probabbly because of improper fine distribution in granules.
    Investigation related to material.
    Used material for compression activity from approved source and details as mentioned below;
    Sr. No.
    Description
    Material code
    SAP code
    Issued Qty for compression

Panfor SR 500 B.no.PAF01421
Metfromin Hydrochloride SR granules 59.88% w/w
3000355
3000082
877.15kg
2.
Panfor SR 500 B.no.PAF01422
Metfromin Hydrochloride SR granules 59.88% w/w
3000355
3000082
881.75kg
3.
Panfor SR 500 B.no.PAF01423
Metfromin Hydrochloride SR granules 59.88% w/w
3000355
3000082
875.20kg
SOP Ref. No. : CQ/003 Page 4 of 4
Format No.: CQ/003/F-03
4.
Panfor SR 500 B.no.PAF01424
Metfromin Hydrochloride SR granules 59.88% w/w
3000355
3000082
877.30kg
Investigation related to equipment and measurement.
Used equipment’s for above said batches already in qualified status. Qualification details are mentioned below;
Sr.no.
Equipment name
Equipment ID
Qualification status
1.
51 station Giga press tablet compression machine
PR049
Qualified
Investigation related personnel.
Involve technician and officer were trained and competent to perform the compression activity.
Investigation related to Environment.
Environmental condition maintained during compression activity were as defined in BMR.
Root Cause:
Probable root cause of incident may be the less dwell time to achieve the desired hardness of tablet. To achieve hardness compression machine speed was reduced.
Corrective Action:
As a corrective action speed of the tablet compression machine reduced and all the parameters checked and found well within the limit. Tablets compressed during initial setting was rejected and sent for destruction.
Risk Analysis:
After speed reduction of tablet compression machine than specified limit all the parameters found well within the specified limit hence there is no impact on the quality of product is anticipated. All compression parameter found complying with specification.
Preventive Action:
As these batches wherein we required to reduce the compression machine speed, hence change control needs to be initiated to revisit the compression machine speed.
Prepared By: Reviewed By: Approved By:


(YOGESH NARKHEDE) #34

Annexure - III
Investigation Report Format I/PR/18/155
Purpose:
Purpose of this incident investigation report is to identify the observed variance in the reconciliation of tablet after packing of product Buspirone Hydrochloride Tablets USP 5 mg.
For Batch number 11718001. Actual transferred tablets for packing was 639635 number and total reconciled tablets were 64932 tablets, variance of 2297 tablets were observed.
Scope:
Scope of this incident investigation is applicable to following;
Product Name: Buspirone Hydrochloride Tablets USP 5 mg
Generic name: Buspirone Hydrochloride tablets USP
Batch number: 11718001
Count: 100 tablets in HDPE.
Batch size: 53.20 kg 700000 tablets
Manufacturing date: Jul.2018
Expiry date: Jun.2020
Background:
Product Buspirone Hydrochloride Tablets USP 5 mg is manufactured on US market for client Apnar Pharma LLP. Product is compressed on Korsch 400 XL compression machine (SP15). After compression, tablets were inspected on Enclony tablet/capsule inspection machine. After inspection and tablets were transferred to packing. Packing of product was carried out tablet/capsule counting machine and tablets were packed in bottle pack of HDPE bottle of 100 tablets.
After packing, as per procedure reconciliation of tablets was done. During review of packing reconciliation, variance of about 2297 tablets was observed between packed quantity and received quantity.
This incident investigation report is initiated to find out the probable root cause and to suggest suitable corrective and preventive action.
Investigation:

  1. Investigation related to Man:
    ➢ Involved person in packing, tablet inspection and compression activity were trained and competent.
  2. Investigation related to Method:
    ➢ Line clearance of compression stage, inspection and packing stage reviewed and previous product of each stage were different and no failure observed.
    ➢ Tablets were counted as per pack size; bulk pack of 100 tablets in HDPE container on tablet /capsule counting machine (PR299 and PR434).
    ➢ After compression, tablets were inspected and the tablets were packed on tablet /capsule counting machine (PR438).
    ➢ Reconciliation of packed quantity reviewed, and following observation noted,
    SOP Ref. No. : CQ/003 Page 2 of 4
    Format No.: CQ/003/F-03
    Sr.No.
    Details
    Total
    1
    Standard batch size
    700000 tablets
    2
    Quantity received from manufacturing
    639635 tablets
    3
    Total quantity packed and transferred to FG stores
    623600 tablets
    4
    Sample (retention+client+stability+analysis+inprocess+other sample+ excise sample)
    400+5300+120+140+1200+3600+5700+100=16560 tablets
    5
    Total yield (3+4)
    640160 tablets
    6
    Reject
    1772 tablets
    7
    Variance (2-(5+6)
    2297 tablets
    8
    Actual yield
    100.08 %
    9
    Theoretical yield in %
    91.45 %
    10
    % reconciliation
    100.36 %
    ➢ Total 260 shipper were packed.259 full shippers and each containing 24 bottles in each and one loose shipper which is containing 20 bottles in shipper. Total 623600 tablets were packed.
    ➢ As a per packing process, in process checks were performed for count verification and bottle speed was kept in the range 8 to 12 bottles per minutes.
    ➢ No error observed in tablet count during packing activity.
    ➢ Reconciliation of all sample is matching. Hence there is less chance to get variation in tablet count during packing activity.
    ➢ Against these observation, tablet inspection stage reconciliation was verified. For tablet inspection actual quantity was transferred as 653149 tablets, after inspection actual quantity 639635 was transferred to packing. Total handling waste was 8043 tablets and total 5471 tablet variance was observed between received for inspection and total inspected tablets. No stoppage or count resetting during inspection activity observed.
    ➢ Compression stage reconciliation was reviewed. Compression stage, number of compressed tablets were calculated by considering average weight of tablets i.e.0.0762 gm. Total tablets were transferred for inspection was 653149 tablets.
    ➢ Compression stage tablet number calculation was done based on the total weight of compressed tablets and average of tablet. There may chances of variation in tablet weight during compression within its specified limit. Standard average weight of tablet was observed 76.2 mg. No error observed in compression stage reconciliation. Compression stage tablet count is ok.
    ➢ Other batches reconciliation data reviewed and variance in tablet transferred to packing and total packed quantity observed.
    ➢ For getting variance between the tablet count after packing and after enclony tablet/capsule inspection machine, all stages reconciliation and practice was reviewed and confirmed that observed tablet count variance is about 0.33 % of total batch size.
    SOP Ref. No. : CQ/003 Page 3 of 4
    Format No.: CQ/003/F-03
    ➢ For observed count variation, observation of count is already taken with OEM Tablet/capsule inspection machine (Enclony).
  3. Investigation related to Equipment:
    ➢ Used equipment for packing, inspection and compression activity are already in qualified status.
    Sr.
    No.
    Equipment name
    Equipment ID
    Qualification done on
    1
    Tablet/capsule counting machine
    PR299
    Oct.2017
    PR434
    Oct.2017
    2
    Automatic tablet/capsule inspection machine (enclony)
    PR438
    Nov.2017
    3
    Compression machine
    (Korsch XL 400)
    PR040
    Sep.2016
    ➢ Used equipment’s found in qualified and preventive maintenance status.
  4. Investigation related to measurement:
    ➢ Compressed tablet were transferred to inspection by doing calculation of weight of compressed tablets and average weight. No error observed.
    ➢ Tablet/capsule counting machine, Automatic tablet/capsule inspection machine counting machine functioning was intended.
    Root Cause
    Exact root cause for observed count variance of tablets not identified. Both the equipment’s are working on count base. No failure observed during inspection or packing activity. Tablets were counted on tablet counting machine and verified its count during in process checks and chance of counting during tablet counting during packing activity can be ruled out.
    Observation of counting error will be taken with OEM and possibility of counting error generation during tablet/capsule inspection machine will be evaluated.
    Corrective Action:
  5. Reference incident number shall be recorded in respective BMR.
  6. Along with number basis calculation, weight basis calculation at inspection stage will be performed for future batches. Based on the observation further preventive action will be defined.
  7. Based on the minimum 10 batches data if required acceptable reconciliation variance limit will be defined.
    SOP Ref. No. : CQ/003 Page 4 of 4
    Format No.: CQ/003/F-03
    Risk Analysis:
    Observation variance reconciliation may have chance count variation packed bottle and it may leads to market complaint. As detection system tablets were packed in bottles in count basis. i.e. 100 count for batch under investigation. This count was verified during packing activity, hence observed reconciliation variance of tablet between total reconciled quantity and transferred quantity. Performed in process check during packing activity were found satisfactory. No previous history reconciliation error available with this product. Hence no risk to packed product observed.
    Preventive Action:
  8. Observation to be taken with OEM of tablet /capsule inspection machine.
  9. During inspection tablets to be transferred on weight basis calculation.
    Prepared

(YOGESH NARKHEDE) #35

Annexure - III
Investigation Report for I/PR/18/143
Purpose:
Purpose of this investigation is to identify the probable root cause and to determine appropriate corrective and preventive actions for observed one blister with pocket cut by IPQA in secondary packing in shipper No. 27.
Scope:
The Scope of this investigation is applicable to
Product name: Telsite 40 mg
Batch No: 0718001 and 0718002
Batch size: 490000
Mfg. date: Jun.2018 & Exp date: May.2020
Equipment name & ID: PG super blister pack machine & PR246
Marketed by: Sanofi India Limited.
Background:
Telsite 40 mg was manufactured at Inventia Healthcare limited for client: Sanofi India Limited.
Compressed tablets were packed on PG super blister pack machine. This was first batch of validation on new change part (punching tool, guide track, Feeding channel, Sieve Plate, Vibrator) layout no. PGB082182017 (Pack Size: 93 X 109).
Material used for trial were Printed Al Foil 101 mm (0.025 mm) (PM Code: 2006984) & Alu-alu Film 101 mm (0.13 mm) (PM Code: 2006869).
Checks performed during trial were NFD count, TB/LB of sealing Plate, base splice count, Lidding material count, Blister stroke, base material type, index length, feeder signals, sealing rejection count, sealing temperature observations, speeds (cuts/min.), feeding, printing, sealing cutting, knurling marks, pick & place activity & leak Test. All performed checks were found satisfactory.
During in process check, by IPQA in secondary packing, one blister with pocket cut was observed in shipper no 27. Hence shipper nos. 1 to 27 were inspected for pocket cut observation.
During inspection of shipper no 1 to 26, no pocket cut observed. In shipper No. 27, pocket cut were observed in 28 blisters. Also there was observation of pocket cut in shipper no 47. Hence Shipper no 47 to 28 were recommended for inspection & among these only one pocket cut blister observed in shipper No.40.
This incident investigation report is initiated to find out the probable root cause and to suggest suitable corrective and preventive action plan and to evaluate the impact.
SOP Ref. No. : CQ/003 Page 2 of 6
Format No.: CQ/003/F-03
Investigation:

  1. Investigation related to Method:
    ➢ Product packing was initiated on PG super blister pack machine ID No. PR246 (Make- IMA PG-India Pvt Ltd). Blistering was carried out (from 29/Jul/2018 to 31/Jul/2018). Blister formation takes place by flat forming & per stroke one blister is formed.
    ➢ This was the first batch of validation on new change part layout no. PGB082182017. Physical condition of the change parts checked by Operator Mr. Manish, production Officer & IPQA Officer was satisfactory.
    ➢ New change part trial was taken before starting of the batch & was satisfactory. During change part trial air pressure was 6 Kg/cm2, sealing temperatures were 150.4 ℃, 165.2 ℃ & 180.5 ℃ (Standard: 150 to 180℃), speed of machine 35 cuts/min, 45 cuts/min & 55 cuts/min (standard. 40 – 55 cuts/min.), no pocket observation noted during trial.
    ➢ Performance checks for camera performed including checking of empty pocket, missing tablets, broken tablets & foreign colour tablets and was satisfactory.
    ➢ Blister Pack machine was set by operator by setting sealing temperature 161.50 ℃ (Limit: 150 to 180℃), speed of machine 44 cuts/min. (limit: 40 – 55 cuts/min.), Air pressure 6 Kg/cm2 (Limit: 5-6 Kg/cm2) & blister quality. Pocket cut was observed near the blister pocket in shipper no 27 during IPQA checking in secondary packing.
    ➢ Possible sources of getting pocket cut observation may be following;
    • Burr formation observation or damaged forming plug and plate
    • Depth of pocket
    • Misalignment and movement of blister forming plate
    • Used aluminum foil
    • Improper Machine setting
    ➢ As a part of investigation forming plate and forming plug were verified and found smooth and there were no burr observed.
    ➢ Depth of pocket as per change part layout mentioned as 4.7 mm and observed depth for each pocket as mentioned below
    ➢ Depth of blister pocket was observed as below and found satisfactory.
    Pocket No.
    Depth in mm
    Pocket No.
    Depth in mm
    Pocket No.
    Depth in mm
    1
    4.60
    6
    4.60
    11
    4.60
    2*
    4.70
    7
    4.60
    12
    4.40
    3
    4.60
    8
    4.60
    13
    4.50
    4
    4.60
    9
    4.60
    14
    4.60
    5
    4.60
    10
    4.60
    15
    4.40
    SOP Ref. No. : CQ/003 Page 3 of 6
    Format No.: CQ/003/F-03
    ➢ Pocket No. 2 marked with * is the pocket observed with cut having depth of 4.70 mm. Against the above tablet thickness was verified, it was observed in the range 3.90 to 4.03 mm. Pocket size and tablet size found satisfactory. Tablet found freely movable in pocket.
    ➢ In one blister 420 blisters are packed. In shipper No. 27 of B. No.0718001 cut pocket observed for 28 blisters. In shipper No. 40, cut pocket observed in One blister.
    ➢ In B. No. 0718002, cut pocket observed in shipper no. 13, 15, 18 & 19- 01 Blister each, in shipper No. 14 – 02 blisters, Shipper 16- 08 Blisters & shipper No. 17 – 04 blisters.
    ➢ Machine setting was verified and no error observed. Possibility of jerk or misalignment to the forming plate and sealing station and no error observed. Investigation details were mentioned in brief in equipment related investigation.
    ➢ Use aluminium foil roll and its details as mentioned below;
    ➢ Ptd. Al. foil 101 mm (SAP Code: 2006984) and Alu-Alu film 101 mm (SAP Code: 2006869).
    Material Description
    Material Code
    AR No
    Qty. Dispensed
    Printed Al Foil 101 mm (0.025 mm)
    2006984
    10000247357
    26.2 Kg
    Printed Al Foil 101 mm (0.025 mm)
    2006984
    10000247369
    10.0 Kg
    Alu-alu Film 101 mm (0.13 mm)
    2006869
    10000245067
    104.24 Kg
  2. Investigation related to equipment and measurement:
    ➢ Blister Pack machine i.e. PG super machine (ID No. PR 246) was used for blistering of telsite
    tablets.
    ➢ Blister machine is qualified on 28/Jun/2010, recently re-qualified on 31/Mar/2018.
    ➢ Preventive maintenance of machine was done on 28/May/2018 & is due in Aug/2018.
    ➢ Forming locking dia pin was broken two times on date 02/Aug/2018 & was replaced by new
    pin by engineering department.
    ➢ New change part trial was taken before starting of the batch & was satisfactory.
    ➢ Two studs were used to hold the change part (layout No. PGB082182017) as per engineering
    locally made part will not have any direct bearing on pocket cut issue.
    ➢ Forming locking dia pin may have become loose during the course of use, this may be the
    probable root cause for getting the pocket cut formation, this may lead to higher pocket depth during batch run and pocket cut formation get generated Identified probable cause may not be the exact root cause but with high degree of confidence and 100 % inspection of blister further packing activity was completed.
  3. Investigation related to material:
    ➢ Issued packing material are from approved source. Packing material were testing prior release for usage and approved by QC.
    SOP Ref. No. : CQ/003 Page 4 of 6
    Format No.: CQ/003/F-03
    ➢ Foils used in product were Ptd. Al. foil 101 mm (SAP Code: 2006984) and Alu-Alu film 101 mm (SAP Code: 2006869).
    Material Description
    Material Code
    AR No
    Qty. Dispensed
    Printed Al Foil 101 mm (0.025 mm)
    2006984
    10000247357
    26.2 Kg
    Printed Al Foil 101 mm (0.025 mm)
    2006984
    10000247369
    10.0 Kg
    Alu-alu Film 101 mm (0.13 mm)
    2006869
    10000245067
    104.24 Kg
    ➢ Issued packing material are from approved source. Packing material were testing prior release for usage and approved by QC.
    ➢ New change part trial was taken before starting of the batch & was satisfactory.
    ➢ Alu-Alu film 101 mm (SAP Code: 2006869) details from the SAP as follows.
    Supplier/Vendor- ACG Pharm pack Pvt. Ltd.
    ➢ Al. Foil consist of foil with text matter printed on dull surface of aluminium ( with NC coating ) & VMCH coating on other side. Following are the test, Specification & observation details:
    Test
    Specification
    Results
    Description
    Non-toxic rigid multi-layered Alu Alu film
    Non-toxic rigid multi-layered Alu Alu film
    Total Foil Thickness
    0.12 to 0.14 mm
    0.138 mm
    Thickness of OPA ( Oriented Polyamide)
    0.023 to 0.028 mm
    0.026 mm
    Thickness of Aluminium
    0.041 to 0.050 mm
    0.049 mm
    Thickness of PVC (Polyvinyl chloride )
    0.054 to 0.066 mm
    0.064 mm
    Total Grammage
    219.32 to 263.02 g/m2
    253.55 g/m2
    Presence of Layers
    Check presence of three layers OPA, aluminium & PVC.
    Three layers OPA, aluminium & PVC present.
    Sr. No.
    Vendor batch number
    AR number
    Used in batch number
    Observation
    1
    0000065072
    10000245067
    0718001
    Pocket observation
    2
    0000065072
    10000245067
    0718002
    Pocket observation
    SOP Ref. No. : CQ/003 Page 5 of 6
    Format No.: CQ/003/F-03
    Test
    Specification
    Results
    Width of Film
    100 to 102 mm
    101 mm
    Internal core diameter
    74 to 76 mm
    76 mm
    Overall diameter of Roll
    Maximum 400 mm
    370 mm
    Core material
    Aluminium/PVC
    PVC
  4. Personnel:
    ➢ All operators & supervisors involved in packing activity were trained & competent.
  5. Investigation related Environment:
    ➢ Temperature, humidity conditions in manufacturing areas were found to be well within specified limits of 19 to 27 deg C and 40 to 65% RH.
    Root Cause:
    Observation of pocket is intermittent and was not continuously, probably may be because of forming locking dia pin become loose during the course of use, this may lead to higher pocket depth during batch run and pocket cut formation get generated. However this may not be exact root cause, but with high degree assurance and 100 % inspection of packed product, there no possibility of packing blister with pocket cut. Incidence is taken up with OEM for further investigation, based on OEM recommendation, action to be worked out.
    Corrective Action:
  6. Blisters were inspected & defective blisters were taken out as rejection, hence only good blisters were allowed for final packing.
  7. Pocket Size recommended to be kept below 4.60 mm & next minimum three batches to be monitored for the pocket depth size.
  8. Matter is taken up with OEM for further investigation & based on OEM observation action planned will be finalized.
    Risk Analysis:
    This observation was noted during in process checks. Hence 100% inspection of packed blisters was carried out. All packing in process parameters were found complying. Used packing material were found complying with specification. Leak test of product found satisfactory. Both batches blisters were inspected for pocket cut observation during packing sand only good blisters were packed. Hence no risk identified to packed product.
    SOP Ref. No. : CQ/003 Page 6 of 6
    Format No.: CQ/003/F-03
    Preventive Action:
  9. Till get the resolution for the observed pocket cut, 100 % inspection during packing activity will be done.
  10. To have auto rejection in case pinhole to the pocket, it is recommended to install pinhole detector.
    Prepared By: Reviewed By: Approved By

(YOGESH NARKHEDE) #36

Annexure III
Investigation Report Format I/PR/18/141
Purpose:
Purpose of this annexure is to investigate the cause for observation of capping in Batch No. PGR0141, PGR0142, desired hardness not achieved in Batch No PGR0143 and friability failed in Batch No. PGR0144
Scope:
The Scope of this annexure is applicable to Proglutrol G2 Batch No. PGR0141, PGR0142, PGR0143 and PGR0144.
B.Size: 515000 tablets.
Mfg.date-Aug.2018
Expiry date: Jul.2020
Marketed by: Healol pharmaceuticals – Malaysia
Background
Incident raised for Proglutrol G2 Tablet Batch No.: PRG0140 at compression stage on compression machine speed of the compression machine mentioned in the BMR is 20 RPM to 30 RPM & hardness limit is 12 Kp to 25 Kp. To achieve tablet hardness and tablet free from capping machine speed is deviated to 17 RPM against BMR speed limit i.e. 20 RPM to 30 RPM.
As a part of CAPA provided against I/PR/18/141 batches under monitoring hence these batches were under monitoring at granulation and compression stage.
In B. No. PGR0141 & PGR0142 capping was observed, In batch No.PGR0143 hardness of the tablets was not achieved to desired specification and in batch PGR0144 desired friability was not achieved. Both the batches were planned for compression at GIGA press 51 station compression machine PR049.
Investigation:

  1. Proglutrol G2 is bi layered tablet with the composition of Metformin hydrochloride SR granules 59.88 % w/w and glimepiride granules 0.93 % w/w. Stages involves in manufacturing process are sifting, granulation, drying, sizing , lubrication and compression.
  2. During initial setting at compression stage for Batch No. PGR0141 capping was observed at compression machine speed 20 RPM.
  3. Hence compression machine speed was reduced to 16 RPM from 20 RPM against the standard speed as specified in BMR 20 to 30 RPM. At 16 RPM speed all parameters was found well within the specified limit.
  4. For Batch No. PGR0141 Metformin hydrochloride SR granules 59.88 % w/w from B.No.PGR0141 (434.250 Kg) and Proglutrol G2-Glimepiride Granules 0.93 % from Batch NO.PGR0141 (111.310 Kg) was used.
    SOP Ref. No.: CQ/003 Page 2 of 4
    Format No.: CQ/003/F-03
  5. Granulation stage parameters for Metformin hydrochloride SR granules 59.88 % w/w from B.No.PGR0141 are as follows,
    a. LOD was 4.41 % (lot I), 4.13 % (Lot II), 4.19 % (Lot III) against the standard limit 3.5-4.5 % W/W.
    b. Co mill speed was 252 RPM (Lot I), 253 RPM (Lot II) and 250 RPM (Lot III).
    c. Amperage reading 29.6 (Lot I), 29.8 (Lot II) and 29.5 (Lot III) against the standard limit 26 to 30.
    d. Drying time 31 min (Lot I), 31 min (Lot II) and 32 min (Lot III).
  6. Granulation stage parameters for Proglutrol G2-Glimepiride Granules 0.93 % from Batch NO.PGR0141 are as follows,
    a. LOD was 3.21 % (lot I), 3.39 % (Lot II), 3.39 % (Lot III) against the standard limit 2.9-3.5 % W/W.
    b. Co mill speed was 118 RPM (Lot I), 118 RPM (Lot II) and 118 RPM (Lot III).
    c. Amperage reading 5.37 (Lot I), 5.38 (Lot II) and 5.40 (Lot III) against the standard limit 5.3 to 5.4.
    d. Drying time 43 min (Lot I), 37 min (Lot II) and 38 min (Lot III).
  7. During initial setting at compression stage for Batch No. PGR0142 capping was observed at compression machine speed 20 RPM.
  8. Hence compression machine speed was reduced to 16 RPM from 20 RPM against the standard speed as specified in BMR 20 to 30 RPM. At 16 RPM speed all parameters was found well within the specified limit.
  9. For Batch No. PGR0142 Metformin hydrochloride SR granules 59.88 % w/w from B.No.PGR0142 (439.400 Kg) and Proglutrol G2-Glimepiride Granules 0.93 % from Batch NO.PGR0142 (111.150 Kg) was used.
  10. Granulation stage parameters for Metformin hydrochloride SR granules 59.88 % w/w from B.No.PGR0142 are as follows,
    a. LOD was 4.37 % (lot I), 3.98 % (Lot II), 4.05 % (Lot III) against the standard limit 3.5-4.5 % W/W.
    b. Co mill speed was 258 RPM (Lot I), 256 RPM (Lot II) and 250 RPM (Lot III).
    c. Amperage reading 29.8 (Lot I), 29.9 (Lot II) and 29.7 (Lot III) against the standard limit 26 to 30.
    d. Drying time 30 min (Lot I), 27 min (Lot II) and 27 min (Lot III).
  11. Granulation stage parameters for Proglutrol G2-Glimepiride Granules 0.93 % from Batch NO.PGR0142 are as follows,
    a. LOD was 3.38 % (lot I), 3.20 % (Lot II), 3.32 % (Lot III) against the standard limit 2.9-3.5 % W/W.
    b. Co mill speed was 118 RPM (Lot I), 118 RPM (Lot II) and 119 RPM (Lot III).
    c. Amperage reading 5.40 (Lot I), 5.38 (Lot II) and 5.37 (Lot III) against the standard limit 5.3 to 5.4.
    SOP Ref. No.: CQ/003 Page 3 of 4
    Format No.: CQ/003/F-03
    d. Drying time 45 min (Lot I), 38 min (Lot II) and 39 min (Lot III).
  12. During initial setting at compression stage for Batch No. PGR0143, maximum hardness was achieved to 8.60 Kp and 11.40 Kp for 02 tablets out of 05 tablets (Refer attachment) and capping was also observed at compression machine speed 20 RPM against the specified limit 12.0 Kp to 25.0 Kp.
  13. Hence compression machine speed was reduced to 15 RPM from 20 RPM against the standard speed as specified in BMR 20 to 30 RPM. At 15 RPM speed all parameters was found well within the specified limit.
  14. For Batch No. PGR0143 Metformin hydrochloride SR granules 59.88 % w/w from B.No.PGR0143 (435.950 Kg) and Proglutrol G2-Glimepiride Granules 0.93 % from Batch NO.PGR0143 (110.68 Kg) was used.
  15. Granulation stage parameters for Metformin hydrochloride SR granules 59.88 % w/w from B.No.PGR0143 are as follows,
    a. LOD was 3.62 % (lot I), 4.32 % (Lot II), 4.30 % (Lot III) against the standard limit 3.5-4.5 % W/W.
    b. Co mill speed was 260 RPM (Lot I), 258 RPM (Lot II) and 258 RPM (Lot III).
    c. Amperage reading 29.8 (Lot I), 29.6 (Lot II) and 29.8 (Lot III) against the standard limit 26 to 30.
    d. Drying time 37 min (Lot I), 35 min (Lot II) and 32 min (Lot III).
  16. Granulation stage parameters for Proglutrol G2-Glimepiride Granules 0.93 % from Batch NO.PGR0143 are as follows,
    a. LOD was 3.06 % (lot I), 3.43 % (Lot II), 3.35 % (Lot III) against the standard limit 2.9-3.5 % W/W.
    b. Co mill speed was 120 RPM (Lot I), 121 RPM (Lot II) and 123 RPM (Lot III).
    c. Amperage reading 5.38 (Lot I), 5.40 (Lot II) and 5.38 (Lot III) against the standard limit 5.3 to 5.4.
    d. Drying time 37 min (Lot I), 35 min (Lot II) and 37 min (Lot III).
  17. During initial setting at compression stage for Batch No. PGR0144, friability was observed out of specified limit i.e. 1.104 % against the standard limit NMT 1.0% w/w at 20 RPM.
  18. Hence speed of compression machine reduced to 15 RPM from 20 RPM, after speed reduction friability observed within specified limit along with all other parameters.
  19. For Batch No. PGR0144 Metformin hydrochloride SR granules 59.88 % w/w from B.No.PGR0144 (432.095 Kg) and Proglutrol G2-Glimepiride Granules 0.93 % from Batch NO.PGR0144 (111.34 Kg) was used.
  20. Granulation stage parameters for Metformin hydrochloride SR granules 59.88 % w/w from B.No.PGR0144 are as follows,
    a. LOD was 4.47 % (lot I), 3.88 % (Lot II), 4.22 % (Lot III) against the standard limit 3.5-4.5 % W/W.
    b. Co mill speed was 250 RPM (Lot I), 252 RPM (Lot II) and 250 RPM (Lot III).
    c. Amperage reading 29.7 (Lot I), 29.6 (Lot II) and 29.8 (Lot III) against the standard limit 26 to 30.
    d. Drying time 35 min (Lot I), 33 min (Lot II) and 35 min (Lot III).
    SOP Ref. No.: CQ/003 Page 4 of 4
    Format No.: CQ/003/F-03
  21. Granulation stage parameters for Proglutrol G2-Glimepiride Granules 0.93 % from Batch NO.PGR0144 are as follows,
    a. LOD was 3.37 % (lot I), 3.38 % (Lot II), 3.29 % (Lot III) against the standard limit 2.9-3.5 % W/W.
    b. Co mill speed was 118 RPM (Lot I), 118 RPM (Lot II) and 121 RPM (Lot III).
    c. Amperage reading 5.38 (Lot I), 5.40 (Lot II) and 5.37 (Lot III) against the standard limit 5.3 to 5.4.
    d. Drying time 40 min (Lot I), 44 min (Lot II) and 42 min (Lot III).
    Root Cause:
    Probable root cause for the incident may be the less dwell time to achieve desired hardness, friability and observation of capping. To achieve these parameters compression machine speed was reduced.
    Corrective Action:
    As a corrective action speed of tablet compression machine reduced. All the parameters checked and found satisfactory. Rejected tablets were sent for destruction.
    Risk Analysis:
    After speed reduction of tablet compression machine than specified limit all the parameters found well within the limit hence there is no impact on the quality of product is anticipated. All compression parameters found complying with specified limit.
    Preventive Action:
    Since this is repetitive observation for respective product, change control needs to be initiate to revisit the tablet compression machine speed.
    Prepared

(YOGESH NARKHEDE) #37

Annexure - III
Investigation Report Format I/PR/18/137
Purpose:
Purpose of this investigation is to identify the root cause and to determine appropriate corrective and preventive actions for reconciliation limit in case of Fluoxetine tablets 60mg B.no. 12218007,12218008,12218009 and less yield for B.no. 12218007.
Scope:
The Scope of this investigation is applicable to
Product Name: Fluoxetine tablets 60mg
Batch no: 12218007,12218008,12218009
Batch size: 54.154 (150000 Tabs)
Mfg. date: Oct.2018 & Expiry date: Sep.2020
Background:
Fluoxetine Tablets USP one of the batch manufacturing in Ambernath site for USA client. The process involve manufacturing is RM sifting, dry mixing, wet granulation,lubrication,compression,coating and inspection. After satisfactory result, batch is transfer to packing. After sizing granules and coating, it was observed that the reconciliation of both stages was out of limit against BMR limit (99- 100%). Therefore, this incidence is raised to investigate reason for reconciliation out of range.
Hence this incident investigation was initiated to find out the probable root cause and suggest suitable corrective and preventive action.
Investigation:

  1. Dry mixing and granulation of fluoxetine tablets USP 60mg B.no 12218007 started on 04/Oct/2018 and completed on 04/Oct/2018. During the reconciliation at sized granules stage it was observed that the reconciliation of batch was 95.03% against BMR range 99 – 100%. After dry mix sample for both lots was sent for analysis. Lubrication of the batch was carried out on 13/Oct/2018 before releasing of certificate of analysis reference no. after dry mix sample.at compression stage 86.02%actual yeild observed against BMR limit NLT 90%.
    After coating the reconciliation was observed 100.33% against the standard yield limit 99% to 100%. And actual yeild observed 85.96% against bmr limit NLT 90%.
  2. Dry mixing and granulation of fluoxetine tablets USP 60mg B.no 12218008 started on 04/Oct/2018 and completed on 05/Oct/2018. During the reconciliation at sized granules stage it was observed that the reconciliation of batch was 98.49% against BMR range 99 – 100%. After dry mix sample for both lots was sent for analysis. Lubrication of the batch was carried out on 13/Oct/2018 before releasing of certificate of analysis reference no. after dry mix sample.
    After coating, the reconciliation was observed 100.51% against the standard yield limit 99% to 100%.
    SOP Ref. No. : CQ/003 Page 2 of 5
    Format No.: CQ/003/F-03
  3. Dry mixing and granulation of fluoxetine tablets USP 60mg B.no 12218009 started on 04/Oct/2018 and completed on 05/Oct/2018. During the reconciliation at sized granules stage it was observed that the reconciliation of batch was 98.01% against BMR range 99 – 100%. After dry mix sample for both lots was sent for analysis. Lubrication of the batch was carried out on 13/Oct/2018 before releasing of certificate of analysis reference no. after dry mix sample.
    After coating the reconciliation was observed within limit i.e. 99.32% against the standard yield limit 99% to 100%.
    Investigation related to process: Granulation
    Fluoxetine tablets USP 60MG B.no.12218007
    Sr.no
    Reconciliation
    1
    Theoretical Batch size = 52.065kg
    2
    Actual Yeild ( Lot I + Lot II ) = 49.20kg
    3
    Yeild in % = 94.49% Limit : NLT 90%
    4
    Sample Quantity for analysis
    a) For inprocess checks =0.006kg
    b) For inprocess analysis = 0.072kg
    5
    Rejects = 0.20kg
    6
    Others = nil
    7
    Recinciliation : 2+4+5+6/1*100 = 95.03 Range = 99% - 100%
    LOD lot 1= 1.23% and lot 02 = 1.26% Limit : NMT 2.5%
    Fluoxetine tablets USP 60MG B.no.12218008
    Sr.no
    Reconciliation
    1
    Theoretical Batch size = 52.065 kg
    2
    Actual Yeild ( Lot I + Lot II ) = 50.89kg
    3
    Yeild in % = 97.74% Limit : NLT 90%
    4
    Sample Quantity for analysis
    a) For inprocess checks = 0.010kg
    b) For inprocess analysis = 0.072kg
    5
    Rejects = 0.31kg
    6
    Others = nil
    7
    Recinciliation : (2+4+5+6/1)*100 = 98.49% Range = 99% - 100%
    LOD lot 01= 1.40% and lot 02= 1.34% Limit : : NMT 2.5%
    Fluoxetine tablets USP 60MG B.no.12218009
    Sr.no
    Reconciliation
    1
    Theoretical Batch size = 52.065 kg
    2
    Actual Yeild ( Lot I + Lot II ) = 50.95kg
    3
    Yeild in % = 97.85% Limit : NLT 90%
    4
    Sample Quantity for analysis
    a) For inprocess checks = 0.006kg
    SOP Ref. No. : CQ/003 Page 3 of 5
    Format No.: CQ/003/F-03
    b) For inprocess analysis = 0.074kg
    5
    Rejects = 0.18kg
    6
    Others = nil
    7
    Recinciliation : (2+4+5+6/1)*100 = 98.01% Range = 99% - 100%
    LOD lot 01= 1.40% and lot 02= 1.33% Limit : NMT 2.5%
    Investigation related to process: For compressed tablets
    Fluoxetine tablets USP 60MG B.no.12218007
    Sr.no
    Reconciliation
    1
    Theoretical Batch size = 52.50 kg ( 150000 Tabs )
    5.Hndling Waste ( d+e ) = 3.485kg
    2
    Quantity of granules Received 51.040 = 141171no.
    d ) Granules left over = 0.410kg
    3
    Sample quality
    Kg
    Nos.
    e ) Rejects (i+ii+iii) = 1.635kg
    a) a) Inprocess sample
    0.077
    220
    Qty.tablets rejected
    Kg
    No.
    b) QC sample
    0.053
    150
    i) During compression
    0.59
    1681
    c) c) Other samples during coating
    Nil
    Nil
    ii) During Inspection
    Nil
    nil
    Total ( a+ b+ c )
    0.13
    370
    iii) Other rejection
    2.485
    nil
    4
    Quality Transfer for next stage = 45.165kg ( 1128748 no. )
  4. Total handling waste = Step 5 + 3a = 3.562kg
    7
    Actual yeild in % ( 3+4)/1100 = 86.02%
    Yeild limit = NLT 90%
    8
    Reconciliation Yeild in % (3+4+5)/2
    100 = 98.72%
    Yeild range = 99% to 100%
    Investigation related to process: For coated tablets
    Fluoxetine tablets USP 60MG B.no.12218007
    Sr.no
    Reconciliation
    1
    Theoretical Batch size = 54.154 kg
    5.Hndling Waste ( d+e ) =Nil
    2
    Actual Yeild ( Lot I + Lot II ) = 46.395kg
    d ) Uncoated tablets left = nil
    3
    Sample quality
    Kg
    Nos.
    e ) Rejects = nil
    a) a) Inprocess sample
    0.368
    102
    b) QC sample
    0.043
    120
  5. Toatal rejects = steps 5 + 3a = 0.368kg
    b) c) Other samples during coating
    nil
    Nil
    Total ( a+ b+ c )
    0.411
    222
    4
    Quality Transfer for inspection kg 46.14kg
    7
    Actual yeild in % ( 3+4)/2100 = 98.04Kg
    Yeild limit = NLT 90%
    8
    Theretical yeild in % ( 3+4)/1
    100 = 85.96 %
    9
    Reconciliation Yeild in % (3+4+5)/2*100 = 100.33%
    Yeild range = 99% - 100%
    SOP Ref. No. : CQ/003 Page 4 of 5
    Format No.: CQ/003/F-03
    LOD lot 01= 2.53% and lot 02= 2.57% Limit : NMT 3.0% (LOD of crushed tablets at 105 degree
    Fluoxetine tablets USP 60MG B.no.12218008
    Sr.no
    Reconciliation
    1
    Theoretical Batch size = 54.154 kg
    5.Hndling Waste ( d+e ) =Nil
    2
    Actual Yeild ( Lot I + Lot II ) = 49.46kg
    d ) Uncoated tablets left = nil
    3
    Sample quality
    Kg
    No.
    e ) Rejects = nil
    a) Inprocess sample
    0.370
    1020
  6. Toatal rejects = steps 5 + 3a = 0.370kg
    b) QC sample
    0.044
    120
    c )Other samples during coating
    Nil
    Nil
    Total ( a+ b+ c )
    0.414
    1140
    4
    Quality Transfer for inspection kg = 49.30kg
    7
    Actual yeild in % ( 3+4)/2100 = 98.57%
    Yeild limit = NLT 90%
    8
    Theretical yeild in % ( 3+4)/1
    100 = 91.80%
    9
    Reconciliation Yeild in % (3+4+5)/2*100 = 100.51%
    Yeild range = 99% - 100%
    LOD lot 01= 2.81% and lot 02= 2.88% Limit : NMT 3.0% (LOD of crushed tablets at 105 degree
    Fluoxetine tablets USP 60MG B.no.12218009
    Sr.no
    Reconciliation
    1
    Theoretical Batch size = 54.154 kg
    5.Hndling Waste ( d+e ) = Nil
    2
    Actual Yeild ( Lot I + Lot II ) = 51.43kg
    d ) Uncoated tablets left= nil
    3
    Sample quality
    Kg
    No
    e ) Rejects = nil
    a) Inprocess sample
    0.260
    721
    b) QC sample
    0.043
    120
  7. Toatal rejects = steps 5 + 3a = Nil
    c) Other samples during coating
    nil
    nil
    Total ( a+ b+ c )
    0.303
    841
    4
    Quality Transfer for inspection kg 50.780kg
    7
    Actual yeild in % ( 3+4)/2100 = 97.96
    Yeild limit = NLT 90%
    8
    Theretical yeild in % ( 3+4)/1
    100 = 94.33
    9
    Reconciliation Yeild in % (3+4+5)/2*100 = 99.32
    Yeild range = 99% - 100%
    LOD lot 01= 2.92% and lot 02= 2.83% Limit : NMT 3.0% (LOD of crushed tablets at 105 degree
    Investigation related to material.
    Used material for Granulation activity from approved source.
    Investigation related to equipment and measurement.
    Used equipment’s for above said batches already in qualified status. Qualification details are mentioned below;
    Sr.no.
    Equipment name
    Equipment ID
    Qualification status

Sifter
PR092
Qualified
2
Paste preparation vessel
PR219
Qualified
3
RMG 150L
PR035
Qualified
4
FBE 125L
PR036
Qualified
SOP Ref. No. : CQ/003 Page 5 of 5
Format No.: CQ/003/F-03
5
Comill
PR037
Qualified
6
Auto coater
PR032
Qualified
Investigation related personnel.
Involve technician and officer were trained and competent to perform the compression activity.
Investigation related to Environment.
Environmental condition maintained during dry mixing, granulation,compression and coating activity were as defined in BMR.
Root Cause:

  1. Probable root cause for less reconciliation at granulation stage is unaccountable loss during sizing of granulation.
  2. Probable root cause for less yeild at compression and coating stage of B.no.12218007 due to unaccuntable loss during granulation and dry mix.
  3. Probable root cause at coating stage reconciliation is may be due to the LOD difference at dry mix & coating stage.
    Corrective Action:
    Theoretical yield which impact the on reconciliation. Hence based upon the trend of sized granules stage BMR to be revised for limits.
    Risk Analysis:
    As the batch processed to next stage after satisfactory result of dry mix and lubrication sample there is no impact on quality of product anticipated.
    Preventive Action:
    As per the trend the reconciliation yield is out of limit hence the Change control needs to be initiated to revisit the reconciliation yield for revised the limit.
    Prepared By: Reviewed By: Approved By

(YOGESH NARKHEDE) #38

Annexure - III
Investigation Report Format I/PR/18/123
Purpose:
Purpose of this incident investigation report is to identify the probable root cause for the observed layer separation during compression activity of product Glyciphage VG1 batch number IA18004.
Scope:
This investigation report is applicable to following
Product name: Glyciphage VG1
Generic name: Metformin Hydrochloride SR 500 mg, Voglibose 0.2 mg & glimepiride 1 mg tablets.
Batch number: IA18004
Mfg. date: May 2018
Exp. Apr.2020
Batch size: 1030000 tablets
Background:
Glyciphage VG1 is one of the products manufactured at Inventia. This is domestic market product for client Franco Indian Pharmaceutical ltd.
The generic product is bilayer tablet with one layer of Metformin HCl SR 500 mg & second layer of voglibose 0.2 mg & Glimepiride 1 mg. These tablets are packed in blister pack on Elmach equipment. The blister pack contains 10 x 2 tablets. During initial first shipper blister verification there was observation of layer separation to the tablets. 02 blisters were observed with layer separation to the tablet.
Earlier observed incident for layer separation were checked for suggested action plan and it was confirmed that dust/ fine generated during compression activity were not added. During granulation, loss on drying was kept in the range 3.5 to 4.5 % w/w for first layer metformin hydrochloride SR granules 59.88 %. For second layer it was kept in the range 1.0 to 2.0 % w/w. During compression activity, machine and parameter setting was done as defined.
During packing activity 02 blisters with defective tablets were observed hence received containers were checked for the observation. Layer separation to the tablet not observed in process container. Conscious decision was taken to inspect the blister during packing online packing and further detailed investigation was extended to manufacturing process.
Investigation:

  1. Batch packing activity of product Glyciphage VG1 batch number PP07 Elmac EPI 2500 machine.
  2. During initial first shipper blister verification there was observation of layer separation to the tablets. 02 blisters were observed with layer separation tablet. Hence received containers were checked for the observation. Layer separation to the tablet not observed in process container.
  3. Conscious decision was taken to inspect the blister during packing online packing.
  4. Initial during batch packing activity, however in packed blister these observation was noted. Initial at the start packing activity machine speed was 27 cuts minutes (limit was 15 to 29 & for this machine speed, vibration speed was on high.
    Compression stage investigation:
  5. Compression data was reviewed and confirmed that batch compression was done on 51 station compression machine.
  6. Compression machine speed was 18 RPM (12 to 25 RPM). Hardness of tablets was observed.
  7. Observed hardness of tablets is 13.70 to 19.20 KP (limit 12 KP to 35 KP) and friability of tablets observed in the range 0.084 to 0.350 % w/w.
    SOP Ref. No. : CQ/003 Page 2 of 4
    Format No.: CQ/003/F-03
  8. During compression activity no such observation noted and during AQL inspection of compressed tablets, no such observation noticed.
  9. Observed dust during compression activity for voglibose and glimepiride granules which was about 5.518 kg and dust of metformin granules which was about 20.200 kg was destroyed and not added.
  10. Initial setting rejection was observed 1.900 kg and in process rejection was observed 2.100 kg, leftover granules of Voglibose and glimepiride granules was observed 0.850 kg and metformin leftover granules were observed 11.500 kg. All these rejection were destroyed.
  11. For compression activity punches used were from box 116, 18x9 capsule shape standard concave, beveled, plain single tip were issued for this batch. Punch set were received on 23/May/2018 and prior issuance, inspection of punches on 24/Jun/2018 was done and used or compression activity. No abnormality observed.
    Evaluation: Compressed tablet parameters were observed complying with specification. No layer separation observation was noted during compression activity. Hardness of tablets was observed lower side to the specification but within the limit.
    Granulation stage:
  12. For first layer granules from Metformin Hydrochloride SR granules 59.88 % w/w batch number A07461848 and A07461849.
  13. Prior granulation Metformin hydrochloride was milled through co-mill fitted with 1.00 mm screen with fast speed. (Used screen as PR/CO-1.0104) in two lots.
  14. Dry mixing, wet Granulation and drying activity was carried out in FBE 1300L in two lots.
    Granulation parameter reviewed and tabulated below;
    Parameter
    Limit
    B.No. A07461848
    A07461849
    Lot 1
    Lot 2
    Lot 1
    Lot 2
    Dry mixing
    Dry mixing time
    25 minutes
    25
    25
    25
    25
    Wet granulation
    Air atomization pressure
    3.5 to 4.0 kg/cm2
    3.6 to 3.7
    3.6 to 3.7
    3.6 to 3.7
    3.6 to 3.7
    Air flow
    500 to 5000 CFM
    999 to 2484
    1377 to 2565
    1134 to 2295
    1053 to 2673
    Spray RPM
    100
    100
    100
    100
    Spray rate
    2.5 to 3.5kg/min
    3.430
    3.43
    3.39
    3.43
    Process time
    40 to 65 minute
    50
    49
    50
    50
    Additional purified water requirement
    NA
    35.00 kg
    35.00 kg
    35.00 kg
    35.00 kg
    Drying
    Air flow
    To be recorded
    1296 to 3213
    1512 to 2484
    1539 to 2376
    1323 to 2673
    Drying time
    To be recorded
    128 minutes
    124 minutes
    122 minutes
    135 minutes
    Observed loss on drying
    3.5 to 4.5 % w/w
    4.03
    4.06
    4.16
    3.96
    Sizing of dried granules
    1.5 mm screen
    1.5 mm
    1.5 mm
    1.5 mm
    1.5 mm
    1.5 mm
    SOP Ref. No. : CQ/003 Page 3 of 4
    Format No.: CQ/003/F-03
    Parameter
    Limit
    B.No. A07461848
    A07461849
    Lot 1
    Lot 2
    Lot 1
    Lot 2
    Lubricated granules
    LOD
    3.5 to 4.5 % w/w
    3.90 % w/w
    4.20 % w/w
    Evaluation:
    Used granules for first layer from batch numbers A07461848 and A07461849 and all parameters are found complying with predetermined BMR specification. Both batches granules manufactured by using FBE method.
  15. Granules of Voglibose 0.089 % & Glimepiride 0.444% w/w batch number A07281804 used as second layer for compression. Granulation activity is carried out in RMG 600.
    Parameter
    Limit
    B.No. A07281804
    Wet granulation
    Binder solution
    47.70 kg
    47.70
    Binder rinsate
    4.02
    4.02
    Binder addition time
    16 to 20 minutes
    18 min
    Mixing time
    1 to 3 minutes
    3 min
    Kneading time
    1 to 3 minutes
    3min
    Ampere reading
    22 to 30 Amp
    24 min
    Total time for granulation
    18 to 26 min
    10 min
    Co mill screen
    1o mm
    10mm
    Drying
    Air flow
    To be recorded
    15 to 20 m/s
    Drying time
    To be recorded
    45 minutes
    Observed loss on drying
    1.0 to 2.0 % w/w
    1.94 %
    Sizing of dried granules
    1.0 mm screen
    1.0 mm
    1.0 mm
    Lubricated granules
    LOD
    1.0 to 2.0 % w/w
    1.59
  16. Yield of batch was observed within the limit i.e. packing yield 99.13 % (limit NLT 88 %) and Final batch yield was 94.29 % (NLT 88 %).
  17. Involved person in granulation, compression and packing activity are trained.
  18. Involved equipment are in qualified status.
  19. During compression activity, hardness and friability were observed complying with specification. Granulation activity is carried out in FBE 1300 hence there may chance of generation of fines during compression activity.
  20. Though observed hardness of compressed tablets observed within the limit i.e. 13.70 to 19.20 KP and observed trend of earlier 2017 APQR batches in the range of 15.90 to 25.70 KP. Current batch hardness is on lower to the specification and trend, which could be because of fine granules.
  21. During packing while feeding of tablet from hopper to feeding channel this leads to generation of minor capping and further layer separation.
    Root Cause:
    Granulation activity was done in FBE 1300, granulation parameter were observed within the defined parameter. No layer separation observation noted during compression activity. Probably may be while feeding of tablets from hopper to feeding channel this layer separation may have occurred.
    SOP Ref. No. : CQ/003 Page 4 of 4
    Format No.: CQ/003/F-03
    During compression activity, hardness and friability were observed complying with specification. Granulation activity is carried out in FBE 1300 hence there may chance of generation of fines during compression activity. Though observed hardness of compressed tablets observed within the limit i.e. 13.70 to 19.20 KP and observed trend of earlier 2017 APQR batches in the range of 15.90 to 25.70 KP. Current batch hardness is on lower to the specification and trend, which could be because of fine granules. During packing while feeding of tablet from hopper to feeding channel this leads to generation of minor capping and further layer separation.
    Corrective Action:
  22. Packing machine speed was reduced to 19 cuts /min.
  23. Manual online inspection of packed blister was done and ensured that no blister with defective tablets.
  24. Finished product analysis results will be checked prior release of batch.
    Risk Analysis:
    Observation was noted at the start of packing activity. All defective blisters were removed and batch packing was completed with more vigilance, less vibration and low machine speed hence no risk identified to product quality. Yield of batch was observed within the defined limit.
    Preventive Action:
  25. Minimum three more batches granulation (Loss on drying and flow properties) and compression activity (hardness and friability) to be monitored for identification of observed tablet defect then further course of action will be planned.
    Prepared By: Reviewed By: Approved By

(YOGESH NARKHEDE) #39

Annexure - III
Investigation Report Format I/PR/18/109 CAPA effectiveness
Purpose:
Purpose of this incident investigation report is to identify root cause of less yield at seal coating stage and Assay at lubrication stage found out of limit.
For Batch number A05251804. Actual yield at seal coating stage found 79.60% (limit 97-100%) and at lubrication stage Assay found 93.6 (limit 95-105%)
Scope:
Scope of this investigation is applicable to following;
Product Name: Pantoprazole Enteric Coated pellets 21% w/w
Generic name: Pantoprazole Enteric Coated pellets 21% w/w
Batch number: A05251804
Batch size: 98.37 kg pellets
Manufacturing date: Jul.2018
Expiry date: Jun.2020
Background:
Product Pantoprazole Enteric Coated pellets 21% w/w is manufactured as In-hose pellets for Product Prazole plus. Pellets drug coating, seal coating, enteric coating and lubrication done on APCG 600 L. Drug coated pellets followed sifting. On sifted drug coated pellets seal coating suspension sprayed after spraying drying of pellets done. After drying pellets unloaded from bowl and sifting done for seal coated pellets. After that enteric coating suspension prepared and sprayed on seal coated pellets. After enteric coating drying and lubrication done in same equipment. After lubrication pellets unloaded from bowl and sifting done from 12 and 20 mesh then sample withdrawn and send to analysis.
This investigation report is initiated to find out the probable root cause and to suggest suitable corrective and preventive action.
Investigation:

  1. Investigation related to Man:
    ➢ Involved person in drug pellets, seal coating, enteric coating and lubrication activity were trained and competent.
    SOP Ref. No. : CQ/003 Page 2 of 7
    Format No.: CQ/003/F-03
    ➢ Involve sampling person is trained and competent. Sampling performed as per the specified procedure hence sampling error is rule out.
    ➢ Analyst is validated and trained in activity.
  2. Investigation related to Method/Measurement:
    ➢ Drug pellets process parameter found well within specified limit.
    Sr. No
    Parameter
    UOM
    Standard
    Actual

Prewarm the equipment till bed temp reaches to 50℃
NA
NA
2)
Distance between cylinder and mesh
mm
50
50
3)
Spay gun nozzle diameter
mm
1.5
1.5
4)
Silicon tube ID/OD
mm
8/12
8/12
5)
Load the material having RM code 3000161 (NPS)
kg
38.25
38.024
6)
Inlet air temperature (to be adjusted to get desired Bed temp.)

58-66
7)
Bed temperature

40-50
46-48
8)
Exhaust temperature

30-50
43-46
9)
Drive Sped
Hz
20-30
15-19
10)
Inlet air Volume
CFM
500-1200
842-944
11)
Inlet air RH to bed
%
(to be observed)
00-02
12)
Atomizing air pressure
Kg/Cm2
0.5-2.0
1.0-1.2
13)
Needle operation
Kg/Cm2
2.0
satisfactory
14)
Peristatic pump RPM
RPM
10-26
10-20
15)
Spay Rate
Gm/min
80-240
80-160
16)
Start spaying drug binder suspension over the pellets
kg
190.33
190.31
SOP Ref. No. : CQ/003 Page 3 of 7
Format No.: CQ/003/F-03
Sr. No
Parameter
UOM
Standard
Actual
and continue spaying till it is over
17)
Process time
Hrs.
20-22
20 hrs. 27 min
Drying
18)
Bed temperature

40-50
46-49
19)
Exhaust temperature

30-50
43-45
20)
Drying time
Min
20
20 min
21)
Cooling time
Min
10 (or to be done till bed temp. come down to 35 ℃)
20 min
22)
Check LOD at 75 ℃
% W/W
NMT 1.5
0.25
➢ After unloading sifting done pellets yield achieved 99.38 (limit 98 to 100%) hence conclude that drug pellets coating done properly and no loss of API quantity at time of drug loading. No agglomerates found at time of drug loading and at time of sifting.
➢ Parameters observed at seal coating stage are well within specified range.
Sr. No
Parameter
UOM
Standard
Actual
1)
Prewarm the equipment till bed temp reaches to 50℃
NA
NA
2)
Distance between cylinder and mesh
mm
50
50
3)
Spay gun nozzle diameter
mm
1.5
1.5
4)
Silicon tube ID/OD
mm
8/12
8/12
5)
Load the material having RM code 3000161 (NPS)
kg
68.53
67.98
SOP Ref. No. : CQ/003 Page 4 of 7
Format No.: CQ/003/F-03
Sr. No
Parameter
UOM
Standard
Actual
6)
Inlet air temperature (to be adjusted to get desired Bed temp.)

68-74
7)
Bed temperature

40-50
46-49
8)
Exhaust temperature

30-50
42-45
9)
Drive Sped
Hz
20-40
3715-19
10)
Inlet air Volume
CFM
800-2000
1606-1639
11)
Inlet air RH to bed
%
(to be observed)
ok
12)
Atomizing air pressure
Kg/Cm2
0.6-1.8
1.4
13)
Needle operation
Kg/Cm2
2.0
ok
14)
Peristatic pump RPM
RPM
18
18
15)
Spay Rate
Gm/min
425-475
450
16)
Start spaying drug binder suspension over the pellets and continue spaying till it is over
kg
71.61
71.56
17)
Process time
hrs
2 hrs. 30 min-3 hrs 30 min
2 hrs. 40 min
Drying
18)
Bed temperature

40-50
42-48
19)
Exhaust temperature

30-50
43-48
20)
Drying time
Min
20
20 min.
21)
Cooling time
Min
10 (or to be done till bed temp. come down to 35 ℃)
10 min.
22)
Check LOD at 75 ℃
% W/W
NMT 1.5
0.24
SOP Ref. No. : CQ/003 Page 5 of 7
Format No.: CQ/003/F-03
➢ After unloading sifting done pellets yield achieved 79.60% (limit 97 to 100%)
➢ Though parameter recorded for atomizing air pressure is within limit but due to bending of atomizing pipe required atomizing air pressure not achieved at time of spaying result in droplet formation.
➢ Spaying of seal coating suspension started on date 22/Jul/2018 at 05:51 and operator observed agglomerates after 17 min i.e. 06:08. Immediately he was stopped machine and intimate to officer regarding the same.
➢ Till time seal coating suspension spayed around 9.26 kg out of 71.56 kg suspension.
➢ Pellets unloaded from the bowl and sifting done through 12 mesh. After sifting total 14 kg pellets observed above the sieve hence this pellet sends to destruction.
➢ Hence calculation done for proportionate spraying and pellets remaining solution 5.23 kg solution discarded and total 66.33 kg solution sprayed on bed.
➢ Calculation checked, In 9.26 kg suspension solid 0.95 kg present hence 0.95 kg solid sprayed on 67.98 kg drug pellets hence 0.76 kg solid sprayed on 54.90 kg seal coated pellets. 54.90- 0.76 = 54.14 kg pellets remaining.
67.98 = 71.56 kg suspension
54.14 = x
54.14 x 71.56 = 57.00 kg suspension required.
67.98
So total 57+ 9.26 = 66.26 kg total solution to be spayed but total 66.33 kg solution sprayed.
➢ After sifting sealed coating pellets yield observed 60.33 i.e. 79.60%. On basis of yield enteric coating solution calculation done and found correct.
➢ Process parameter at enteric suspension spraying found within specified range. Total process time required to spay 89.51 kg enteric coating solution (standard 112.70 kg) 02 hrs 40 min (2 hrs- 4 hrs)
➢ Drying and lubrication was done in same equipment within specified range.
➢ Drug suspension, seal coating and enteric coating suspensions are continuously stirred for avoiding sedimentation of suspension hence possibility of cake formation is rule out.
SOP Ref. No. : CQ/003 Page 6 of 7
Format No.: CQ/003/F-03
➢ Lab investigation carried out found that calculation error. Reanalysis was done results are
Assay ( Composite )
Limit
20.17 % w/w
18.9%w/w to 23.1% w/w
90.0%– 110.0 % of label claim
96.0% of Label Claim
Assay (Container_1)
19.95 % w/w
95.0% of label claim
Assay (Container_2 )
19.84 % w/w
94.5 % of label claim
3. Investigation related to Equipment:
➢ Used equipment for coating activity is already in qualified status.
➢ Used equipment’s found in qualified and preventive maintenance status.
4. Investigation related to Environment:
All process done within specified temperature and humidity. Process RH found within specified limit.
5. Investigation related to Material:
➢ Dispensing of raw material checked and found all dispensing material dispense as per the batch document and raw material received from approved vendor.
➢ Raw material release after meeting specification hence material root cause is rule out.
➢ API received on 8/May/2018 and used in batch no A05251803 and A05251804. Pantoprazole enteric coated pellets 21% W/W Batch number A05251803 used in product Prazole Plus bacth number A01781803.
Root Cause

  1. Probable root cause for the less yield is bending of atomizing air supply pipes.
  2. Probable root cause of drug loss may be due to attrition of pellets at time of seal coating.
  3. Calculation error
    SOP Ref. No. : CQ/003 Page 7 of 7
    Format No.: CQ/003/F-03
    Corrective Action:
  4. Pipe bending to be taken with OEM. Cheek all pipes of APCG and FBE where atomization required.
  5. Additional sample withdrawn from container number 1 and 2 composite sample. Container 1 and 2 top, middle, bottom composite sample.
  6. Lab error investigation was carried out.
    Risk Analysis:
    Due to less yield not having impact on product quality.
    Preventive Action:
  7. All pipes of Atomizing air replace if there is any bend. Pipes used for atomizing air should be checked prior to every operation. Less bending property pipes to be used.
  8. Consult with OEM feasibility fixing atomizing air pressure sensor near to the atomization point (near to nozzle).
    Prepared By: Reviewed By: Approved By:

(YOGESH NARKHEDE) #40

Investigation Report track under I/PR/18/105
Page 1 of 2
Purpose:
Purpose of this annexure is to capture the details of HMI (PLC) error observed during Sustained Release coating of Venlafaxine SR Pellets 33 % w/w, Batch No. A05651839 with reference to incident number I/PR/18/105.
Scope:
The Scope of this attachment is applicable to -
Product Name - Venlafaxine SR Pellets 33 % w/w
Batch No. - A05651839
Batch Size - 507.50 Kg
Marketed By - EuroPharma Labs, Brazil
Area - PM04
Equipment Name & Equipment ID – APCG 1200c & PR345
Background:
During drug coating stage of Batch no. - 03318002, HMI of APCG 1200c was hanged on 05/Jun/2018 at 3:41. Hence operator pressed emergency button & stopped machine. To find out the root cause Incident Management- I/PR/18/105 were raised. Similar failure was observed in Common Pellets for Duloxetine DR Capsules USP 20 mg, 30 mg, and 60 mg is one the product manufactured at Inventia site. Manufacturing of above said product involves Drug Coating, Barrier Coating and Enteric Coating in APCG 1200c & Lubrication in Octagonal Blender 2000L. After satisfactory results batch transferred to Encapsulation on MG2 followed by packing. During SR coating stage HMI of APCG 1200c was hanged on 11/Sep/2018 at 19:12. Hence operator pressed emergency button & stopped machine. Production person raised the breakdown intimation to engineering to rectify the machine problem
Investigation:
Venlafaxine Sustained Release Pellets 33% w/w, is one of the product manufactured at Inventia site. Stages involved in the manufacturing of above said product are Drug loading & sustained release coating in APCG1200c in single lot & Lubrication in Octagonal Blender 2000l.
During SR coating stage HMI of APCG 1200c was hanged on 11/Sep/2018 at 19:12. Hence operator pressed emergency button & stopped machine. Production person raised the breakdown intimation to engineering to rectify the machine problem.
After restart of power supply HMI started normally. Trial taken of HMI of machine in presence of IPQA and engineering person was found satisfactory. After trial it was observed that process parameter history from 11/Sep/2018 at 18:42 to 21:30 not shown. Till time 19:12 (11/Sep/2018) approximate 474.00 kg SR coating solution sprayed out of 872.68 kg. As corrective action after restarting of HMI partially SR coated pellets were unloaded & sifted through 14 mesh, after sifting 480.90 kg good partially SR coated pellets, 0.718 kg
Investigation Report track under I/PR/18/105
Page 2 of 2
above 14 mesh agglomerates & 0.108 kg handling waste ware observed. Remaining SR coating process were started after sifting. Hence no impact on product quality.
Root Cause:
Equipment/Machine failure.
Corrective action:

  1. Agglomeration observed to be sent for destroyed.
  2. Partially SR coated Pellets sifted through 14# mesh.
    Risk analysis:
    No risk to product quality as batch will be only released after finished product specification. As lubricated results found satisfactory hence no impact on product quality.
    Preventive action:
    Preventive action provided against incident I/PR/18/105 need to take urgent action.

(YOGESH NARKHEDE) #41

Annexure - III
Investigation Report Format I/PR/18/071
Purpose:
Purpose of this incident investigation is to identify cause for observed variance more than limit i.e.2.73 % (limit NMT 2.0 %) in Cap reconciliation.
Scope:
This document is applicable to product Metformin Hydrochloride Extended release tablets 500 mg Batch number 03118094
Pack size: 1x500 counts in HDPE container.
Mfg. date: March.2018
Exp. date: Feb.2020
Background:
Product Metformin Hydrochloride Extended release tablets 500 mg Batch number 03118094 packing activity was initiated on countec bulk packing machine. Required quantities of packing materials were issued as per batch requirement. Batch packing activity was completed as per procedure. After completion of packing activity, rejected material were destroyed and no balance material observed. Batch packing activity was initiated on 10/Apr/2018 and completed on 11/Apr/2018. While performing reconciliation of caps in batch packing record, 52 number excess caps was observed. Previous observed incident I/PR/17/109, for cap reconciliation and suggested CAPAs were checked and confirmed that each closure /Caps are counted on counting machine at supplier end (i.e. Shriji polymer) and after earlier random verification of received consignment was checked and confirmed that there is no count variation. After this incident return material quantity physical counting practice is started. After implementation of this action plan again one more incident was observed where in total packed /reconciled cap quantity i.e. Actual total packed quantity was 1955 number and actual dispensed quantity was 1903 number. About 52 excess caps were reconciled in BPR and variance observed more than 2 % (-2.73 %).
Hence incident investigation is initiated to find out the probable root cause and suggest the suitable preventive action.
Investigation:

  1. Reconciliation of issued caps for batch investigation was reviewed and observed that about excess 52 caps were observed. About -2.73% variance was observed in reconciliation. (Refer BPR reconciliation).
  2. Actual 1809 bottles were packed (Including retention, in process and excise sample) and transferred BSR and no error observed in that. 146 caps were rejected during packing activity and same were destroyed. No material return send from this batch.
  3. For this batch total caps were issued 1903 numbers from QC batch number 0000062662.For this caps were issued from return materials from batches mentioned below;
    SOP Ref. No. : CQ/003 Page 2 of 3
    Format No.: CQ/003/F-03
    Batch number
    Cap QC batch number
    Issued quantity
    (Number)
    Packed quantity in batch (Number)
    Rejection
    (Number)
    Return quantity
    (Number)
    Return quantity issued for batch number
    Remark
    03118088
    0000062662
    2400
    (800x03 pack)
    1833
    18
    575
    03118094 Issued quantity :575 number
    NA
    03118089
    0000062662
    3200 (800x4 Pack)
    1854
    35
    1328
    03118094 Issued quantity :1328 number
    For batch excess quantity was issued and this leads to excess number returned material
  4. All returned Caps from earlier batches were issued for this batch.
  5. As per procedure, packing material (Caps) are issued intact box and they are not counted prior issuance. Issued caps were from return material of earlier batches and these quantities may be not properly counted by concerned prior giving return to stores.
  6. On further investigation it was confirmed that in supplier box (in each intact box of 800 caps). Caps were issued intact as it was in box. After earlier incident no further variation in cap observed.
  7. Observed excess quantity of caps may be not exactly counted while material return or there was counting error happened at the time of material return of earlier batches. This may be the manual error occurred while counting the material to be returned. Returned quantities count mentioned on label was verified prior issuance of caps to the next batch.
  8. Since packed quantities of bottles and Caps in shipper observed in compliance with BPR. Hence no risk to the packed quantities.
  9. Involved person are trained and competent.
  10. Previous packed batch details checked and confirmed that before packing 500 count, batch number 03118097 (bottle pack of 100 count) was taken. Prior taking batch under investigation for packing proper line clearance was taken. Hence chance of extra remaining quantity of caps from previous packed batch can be ruled out.
    SOP Ref. No. : CQ/003 Page 3 of 3
    Format No.: CQ/003/F-03
    Root Cause:
    Observed error in Cap reconciliation may be because of issued material were from return material of earlier batches and intact boxes were issued for earlier batches (03118088, 03118089). There may be chance of counting error might have happened while manual counting of caps which leads to return of physically extra quantities. This may happened because of excess caps were issued than required to batch packing and after packing more number of caps were remained. All these excess returned caps may got issued to batch under investigation and these return material quantities were not counted physically.
    Personnel/Man error (Cap counting error)
    Corrective Action:
  11. Instructed concerned to verify the return quantities properly prior giving to stores and retraining will be imparted to concerned to avoid such error in future. More vigilance is required while physical counting of return material.
  12. Next 10 batches caps dispensing to be done by issuing two intact boxes of 800 caps and remaining quantity will be issued by counting balanced required quantity. Based on the observation of 10 batches further action plan to be decided.
    Risk Analysis:
    Caps were dispensed as per bill of material. Bottles were packed as per requirement. No variation observed in packed quantity. No error observed withdrawn sample quantity. No material returned to stores from batch under investigation. Though there is variance in cap reconciliation, required quantity was packed as per process order requirement.
    Preventive Action:
  13. Awareness to create among all involved person to ensure correct counting of packing materials prior sending to stores.
  14. Retraining to be imparted to all concerned involved person in dispensing of packing material and instructed concerned to issue only near about required quantity asked to ensure this quantity should not be less than required quantity and not to issue extra quantity.
    Prepared By: Reviewed By: Approved By