Investigation of incident


(YOGESH NARKHEDE) #1

Annexure - III
Investigation Report Format I/QA/18/034
Purpose:
Purpose of this incident investigation to identify the probable root cause for observed lubricated granules yield i.e. 101.53 % more than the specified limit in BMR i.e. 96 to 100 % for product Common blend for fenofibrate capsules USP (Micronized) 67, 134 and 200 mg.
Scope:
This incident investigation is applicable to following;
Product name: Common blend for fenofibrate Capsules USP (Micronized)
Generic name: Common blend for fenofibrate Capsules USP (Micronized)
Batch number: 12818003
Batch Size: 177.84 Kg
Client: Amerigen pharmaceuticals, USA market.
Background:
Common blend for Fenofibrate Capsules USP (Micronized) 67 mg, 134 mg and 200 mg is one of the product manufactured in Inventia Healthcare Ltd. at Ambernath plant for client: Amerigen Pharmaceuticals (USA market).
Manufacturing process are involved sifting, dry mix, wet granulation, drying, sifting, milling, blending & lubrication. After lubrication stage, Standard yield was calculated and it was found more than specified limit. Standard yield: 100.53% (Limit: 96%-100%).This observation was noted during batch record review at client end.
Hence this incident management is raised to investigate the probable root cause for getting less yield and to suggest suitable corrective and preventive action.
Investigation:
Brain storming was carried out and identified following probable reason for getting higher yield.

  1. Quantity of milled granules transferred to lubrication
  2. Batches run in campaign and probably may be during granulation and drying previous batch material in small quantities may carry forward in next batch.
  3. Lower loss on drying and more holding time before lubrication
  4. Difference in specified yield limit for milled granules limit is 95 to 101 % and lubricated granules limit is 96 to 100 %.
    To identify the probable cause batch manufacturing record review was carried out.
    ➢ Input material for each stage i.e. wet granulation, drying, sizing and lubrication is carried .Weight recorded at each stage for each material verified.
    ➢ Loss on drying of granulation lot was checked against the mentioned specification i.e. NMT 1.0 % w/w and observed loss on drying in batch under investigation was 0.76 % w/w. Loss on drying was observed well within specification.
    ➢ Quantity of milled granules transferred for lubrication was verified. Yield of milled granules was observed 100.7 % (limit is 95% to 101%) which was within specified range. But yield of milled granules comparatively more than previous two batches (For B. no. 12818001-97.02% and for B.no.12818002- 97.13%). B.Nos.12818001,
    SOP Ref. No. : CQ/003 Page 2 of 4
    Format No.: CQ/003/F-03
    12818002, 12818003 were manufactured in campaign and batch under investigation was the last batch in campaign.
    ➢ Previous product/batches manufactured and its yield was checked and observed that in one campaign after product changeover yield of milled granules of first batch observed lower comparatively to the last batch in the same campaign.
    Data of input material, loss on drying of dried granules, milled granules output is compared and tabulated on next page.
  5. Holding period of dried granules to lubrication stage checked and found that activity was in continuous and holding of material was not observed till lubrication activity. Hence yield because of intermittent storage/holding of granules. Lower loss on drying and more holding time before lubrication and may be in between, weight gain by granules is ruled out.
    ➢ At milling stage handling waste was 0.42 kg is less as compared to previous two batches (For B. no. 12818001-1.50kg and for B.no.12818002- 1.20 kg). At milling stage less losses observed as compared with earlier batches. This may be one of probable cause for getting more yield at milled granules stage.
    ➢ Batches run in campaign and on preliminary investigation it was observed before first batch in campaign product changeover was taken and later on batch to batch changeover was taken. At the time of line clearance it was ensured that no remnant of previous batch present. Procedure is in place hence possibility of small quantities carry forward in next batch is minimum or less. It doesn’t have significant impact on yield.
    ➢ Another probable reason may be variation in specified yield limit for milled granules limit is 95 to 101 %) and lubricated granules limit is 96 to 100 %. After milling, yield of milled granules of batch under investigation was 100.7 % which was well within the milled granules yield specification.
    ➢ As mentioned in BMR, if yield of milled granules observed less than 98 % then further lubricant quantity calculation shall be done. In this case yield was more than 100 % hence no further calculation was required and mentioned quantities of excipient in bill of material were dispensed as it was. Hence with addition of lubricant quantities, chance of yield more than 100 % is obvious. Which is more than the mentioned BMR limit
    ➢ Yield limit for sized granules and lubrication stage were made stringent in the batch under investigation against the change control number C/QA/18/025. 12817001to 12817006 are the validation batches. 12818001 to 12818003 are the normal batches.
    SOP Ref. No. : CQ/003 Page 3 of 4
    Format No.: CQ/003/F-03
    Comparison data of granulation and lubrication activity:
    B. No.
    Lot No. ( LOD in % w/w)
    NMT 1.0 % w/w at 60 °C
    Sized Granules Wt. (Kg.)
    Handling Waste (Kg.)
    Total sized granules Wt. in Kg ( Std. Qty.: 159.69 Kg)
    Sized Granules
    ( % yield)
    Limit 95 to 103 %
    In-process Samples
    Lubricated Granules wt. ( Kg)
    Lubricated Granules
    ( % yield)
    Limit 94 to 103 %
    In-process Samples
    ( Kg)
    Rejection during Lubrication
    1
    2
    1
    2
    12817001
    (Validation batch)
    0.57
    0.89
    76.64
    80.20
    1.00
    156.84
    98.5
    0.849
    173.50
    97.85
    0.522
    0.200
    12817002
    (Validation batch)
    0.75
    0.68
    75.76
    81.36
    0.800
    157.12
    98.67
    0.452
    173.69
    97.96
    0.526
    0.210
    12817003
    (Validation batch)
    0.89
    0.78
    76.84
    80.78
    0.700
    157.62
    98.98
    0.447
    174.43
    98.37
    0.523
    0.350
    12817004
    (Validation batch)
    0.59
    0.86
    74.40
    79.80
    0.750
    154.20
    96.84
    0.04
    170.90
    96.42
    0.581
    0.000
    12817005
    (Validation batch)
    0.71
    0.43
    78.70
    80.00
    0.320
    158.70
    99.66
    0.04
    175.03
    98.71
    0.521
    0.000
    12817006
    (Validation batch)
    0.87
    0.76
    76.60
    80.40
    0.760
    157.00
    98.6
    0.04
    174.30
    98.3
    0.522
    0.000







Limit 95 to 101 %


Limit 96 to 100 %


12818001
0.62
0.78
70.52
84.42
1.500
154.94
97.02
0.00
172.36
96.98
0.115
0.000
12818002
0.53
0.84
74.52
80.60
1.200
155.12
97.13
0.00
172.21
96.90
0.115
0.000
12818003
0.82
0.76
71.58
89.24
0.420
160.82
100.7
0.00
178.68
100.53
0.115
0.005
SOP Ref. No. : CQ/003 Page 4 of 4
Format No.: CQ/003/F-03
Evaluation:
During sizing of dried granules less handling waste observed in comparison with earlier batches. This leads to more yield at sizing stage but within the limit i.e. 100.7 % (limit was 95 to 101 %) however on further addition of lubricant it was observed to 100.53 % which is out of limit of yield at lubrication stage (limit 96 to 100%).
Root Cause:
Yield observed at milled granules stage was 100.7 % which was within its specification limit. After addition of lubricants it observed 100.53 %. This was out of specification.
Yield at sizing stage observed higher may be because of less handling waste in comparison with earlier batches trend. No losses observed during lubrication activity.
Corrective Action:

  1. Reference incident number shall be mentioned on BMR.
  2. Finished product analysis results with respect to assay and related substance of capsules checked and found complying and in line with trend.
    Risk Analysis:
    Yield observed marginally higher at lubrication stage, analysis of lubricated granules and finished product found complying. No risk identified to granules quality.
    Preventive Action:
    Based on next 10 batches data, yield limit to be revisited

(YOGESH NARKHEDE) #2

Annexure - III
Investigation Report Format I/QA/18/029
Purpose:
Purpose of this incident investigation report is to identify the probable root cause for observed one
intact tablet with half broken tablet in blister. This observation was identified during AQL checking
in shipper number 12.
Scope:
This investigation report is applicable to following
Product name: Telmisartan tablets USP 80 mg.
Batch number: 06318014.
Mfg. date: Oct.2018.
Exp. Sep.2020.
Batch size: 245000 tablets.
Pack size: Alu-Alu Blister pack of 10 tablets.
Background:
Telmisartan tablets USP 80 mg is one of the products manufactured at Inventia and marketed by
for Ascend Laboratories.
These tablets are packed in blister pack on PG super blister machine (Equipment I.D. - PR246).
The blister pack contains 10 Tablets in Alu-Alu blister pack (Child Resistant). In secondary packing
online overprinting activity was carried out on each carton and each carton was weighed and then
packed in shipper. After shipper packing AQL activity was performed.
Batch packing activity was started on 03/Nov/2018 with proper verification all batch packing in
process checks for overprinting carton are found complying with specification.
During AQL checking shipper no.12 of batch 06318014 observed one and half broken tablet was
observed in one blister.
Hence this incident investigation is initiated to find out probable root cause and provide corrective
and preventive action against this failure.
SOP Ref. No. : CQ/003 Page 2 of 5
Format No.: CQ/003/F-03
Fish bone diagram for root cause identification:
One and half broken tablet
in pocket
Man Material
Machine &
Measurement
Method
Pocket size
Feeding Channel
condition and setting
Camera setting
Machine
speed/Vibration
Training
Manual
intervention in
setting
Broken tablet
in hopper and
container
Hardness and
friability
Method of tablet
inspection
Storage of
tablets
Method of tablet
loading in hopper
Environment
No contribution of
environmental factor
SOP Ref. No. : CQ/003 Page 3 of 5
Format No.: CQ/003/F-03
Investigation:
Investigation related to Man:
Involved person are trained and competent on blister packing activity.
Machine setting was ensured prior initiation of packing activity. No manual intervention
observed during packing activity, which will not lead to generation of blister with one intact
and one half broken tablet in pocket.
One of the probable reason is it might be generated because of improper setting of feeding
channel.
Investigation related to Material:
Another possibility of generation of broken tablet may be lower hardness of the tablet. Hence
compressed tablet hardness during compression activity was checked and it was found that 9.2
to 12.0 (limit 7 to 15 Kp).
Batch was compressed on 24/Oct/2018 and taken for packing 03/Nov/2018 within the defined
hold time period of compressed tablet. Total 04 in process container were transferred to packing
and in issued container there were no observation of broken tablet. Storage of tablet was done
as per defined procedure.
After receipt of observation of broken tablet, tablets in hopper and containers were checked and
no such broken tablet was observed.
Investigation related to Method:
After compression, tablets were inspected by using automatic tablet/Capsule inspection
machine (Enclony inspection machine). After inspection no broken tablet observed.
Tablets were loaded in hopper manually and there were no broken tablet observation noted.
Investigation related to Machine and measurement:
Blister packing activity was initiated on PG super blister pack machine (Equipment ID PR246).
Change part of layout number 101CI0060037 REV 1 pack size: 123 mm X69 mm were issued
for packing activity.

SOP Ref. No. : CQ/003 Page 4 of 5
Format No.: CQ/003/F-03
Equipment Rotovac blister pack machine and its blister inspection system is already in qualified
status (PR246), last date of re-qualification: Mar-2018. Preventive maintenance of equipment
was done as per scheduled frequency.
For observed defect of one and half tablet, pocket size mentioned on layout was checked and
depth of pocket (TB) was observed 5.6 mm and length of pocket was mentioned as 25.5 mm.
Depth of pocket was set as per product requirement.
Temperature and sealing plate, speed of machine, air pressure recorded during initial setting
and packing activity found satisfactory.
Parameter Standard parameter Actual parameter
Temperature of sealing plate 200 to 220°C 218.2°C
Speed of machine (Cuts/Min) 20 to 35 32
Air pressure (Kg/Cm2) 5 to 6 6
Blister quality and
perforation
Should be good Good
Feeding channel and its setting was checked as a part of investigation. In feeding channel, total
04 feeding track were available. Singling unit is provided to feeding channel to have delivery
of single tablet in pocket. This unit is operated pneumatically. During operation, there might be
chance of SS plate struck of singling unit of feeding channel to the tablet during feeding activity
which may leads to additional broken tablet in blister cavity. In one pocket, one and half tablet
was packed and in other pocket, some piece of broken tablet was packed.
After packing, these pockets were inspected under Camera inspection system and it was not
identified and rejected by camera.
Camera inspection system and its performed challenge test for empty blister, one tablets
removal from blister, blister container one broken tablet, one foreign color tablets in blister and
blister with all good tablets were checked and found satisfactory. To find out cause for nondetection
of additional broken tablet in blister pocket, camera light source and lens were
checked and observed some product dust on light source and camera lens. Due to this, blister
image was not clear which may lead to non -detection additional broken tablet in blister cavity.
Investigation related to Environment:
Environmental condition maintained during manufacturing and packing as per defined and no
contribution because of environmental condition observed to this incident.
Evaluation:
Change parts used for packing activity as mentioned in BPR. Machine setting was done as per BPR.
Tablet might have broken during feeding and because of stroke SS plate of singling unit of feeding
channel and this leads to breakage of tablet. One and half tablet in blister pocket was not identified
by camera due to no clear image of blister. This was Alu-Alu blister pack and hence not identified
during online checking of blister as well.
SOP Ref. No. : CQ/003 Page 5 of 5
Format No.: CQ/003/F-03
Root Cause:
Machine:
Tablet might have broken during feeding and because of stroke of SS plate of singling unit of
feeding channel. Further camera light source and lens were checked and observed some product
dust on light source and camera lens. Due to this, blister image was not clear which may lead to
non -detection additional broken tablet in blister cavity.
Corrective Action:
Existing packed blisters till shipper number 18 were weighed on balance (Weighing range 8.00
to 8.25 gm) and ensured that there were no additional half broken tablet packed in blister.
Resetting of feeding channel was done and one dedicated person kept on machine to ensure
absence of half broken tablet in pocket of blister and after this no similar observation noted.
Retraining will be imparted to concern to have proper feeding channel and its SS plate setting
of singling unit.
Risk Analysis:
All defective blisters were removed and batch packing was completed with more vigilance, 100%
inspection and weighing of individual blister was done till shipper number 18. Hence no risk
identified to product quality. Yield of batch was observed within the defined limit.
Preventive Action:
During batch to batch and product to product cleaning, camera lens and light source to be
cleaned to have clear image of blister pockets. Equipment operation SOP to be updated and
training to be imparted to concern persons. TCD: 31-Dec-2018.
Matter taken with change part manufacturer for feasibility of modification feeding channel :
TCD: 31-Dec-2018.
Prepared


(YOGESH NARKHEDE) #3

Annexure - III
Investigation Report Format
Purpose:
The primary purpose of this investigation is to investigate the root cause and to determine appropriate corrective and preventive action for below mentioned incidence.
Scope:
The scope of this incident is limited for following issues occurring with PVP:

  1. Protocol remains in queue for long time.
  2. For PVP/TAB/322, version no. 1.0 on first page signature and footer was not appeared
  3. For PVP/GRN/197, from page no. 1 to 13, on footer printed by, print date, copy no. and controlled copy not appeared ( From page no. 14 footer is ok)
    Background:
    As per process validation SOP QA/044 Effective date.(12/Aug/2018) : PV protocol shall be prepared in DMS, but while preparation of process validation protocol in DMS system user has faced some issues.
    Investigation:
    IT investigated the issue and raise ticket for issue number 1 in Educe support website. For issue number 2 and 3 IT provided solution to end user.
    Root Cause:
    Observation number 1: Protocol remains in queue for long time
    As per the feedback received from Educe support team, when document comes to author he/she has to start from the Author edit screen to create main document. In this scenario, user has directly clicked on Author attachment screen without submitting the main document on the Author edit screen.
    Due to this there was inconsistency in the data and the document got stuck in queue.
    Observation number 2: PVP/TAB/322, version no. 1.0 on first page signature and footer was not appeared
    IT found out that author has copied/pasted the content from other document and not used standard template which is configured in DMS. Due to which custom variables on first page were removed. Hence the values haven’t appeared on document.
    Observation number 3: PVP/GRN/197, from page no. 1 to 13, on footer printed by, print date, copy no. and controlled copy not appeared ( From page no. 14 footer is ok)
    SOP Ref. No. : CQ/003 Page 2 of 2
    Format No.: CQ/003/F-03
    IT found out that author has copied/pasted the content from other document and not used standard template which is configured in DMS. Also author has used Section break before page number 14, Due to which all the pages till 1 to 13 are having incorrect formatting.
    Corrective Action:
    Educe support team has resolved the document locked in queue issue. For documents PVP/TAB/322 and PVP/GRN/197 new version have been created.
    Risk Analysis:
    Though their are formatting issues are same, technical data of the document remains same. Hence there isn’t any impact on generated document.
    Preventive Action:
    Educe support team has resolved the issue of document locked in queue and will share patch by 30/Nov/2018.
    Training to end user needed to be provided to avoid any future issues.
    Prepared

(YOGESH NARKHEDE) #4

Preliminary investigation:
During AQL inspection, one unsealed bottle was observed in shipper number 96.On receipt of unsealed bottle observation, physical verification of pack was done and confirmed that bottle was found unsealed. No evidence of induction sealing was observed on cap and wad was found intact as earlier in cap. Packed tablet count was found 500 count.
Personnel/Man:
 Involved operator for bulk packing activity was Mr Raju Bhoir. Interaction was done with operator and come to know that there were no major stoppages during induction sealing activity.
 Involved person is already trained and competent on packing activity and equipment operation.
Material:
 Induction sealing cap (SAP code 2003324) of QC batch number 0000067107 (409 numbers) and 000067108 (1441 numbers) were used for packing activity. Vendor for Cap is Shriji polymer. Physical condition of cap with wad of unsealed bottle was checked and found satisfactory.
Environment:
 Temperature and relative humidity of packing area was observed within defined limit (Temperature: 23.8 °C limit is 19 to 27 °C and Relative humidity: 51.8 % (Limit 40 to 65 %).
Equipment and Process:
 Equipment Induction sealing machine is in qualified status (Equipment ID PR302, Qualification done on Nov.2017).
Machine setting and In process checks:
 Machine setting parameter recorded at initial and during in-process checks i.e. % sealing power (70 %) Distance between cap and induction sealing head (4 mm), speed of conveyor (30 BPM) and it was constant throughout the packing operation.
 Alarm and interlocks for induction sealing machine verified during qualification activity for bottle jamming, No foil detector, low flow and high temperature and recorded observation found satisfactory.
 As a part of machine pre-operational challenge test for capping machine and induction sealing machine was done as mentioned below;

Sr.No. Details of challenge test Acceptance criteria Observation during pre-operational checks Inference
Equipment :Rotary capping machine

1 Remove the cap and pass the bottle through sensor Without cap sensor detect bottle there is no cap bottle should get rejected No cap bottle rejected Test was passing
2 Remove the foil from cap and pass the bottle through sensor Without foil cap sensor detect bottle there is no foil in cap and bottle should get rejected No foil in cap and bottle get rejected Test was passing
3 Pass the bottle having tilted cap through sensor Tilted cap sensor detect tilted cap and reject the bottle Tilted cap bottle get rejected Test was passing
4 Manual checking of cap tightness Cap should be fitted tightly on bottle Cap fitted tightly on bottle Test was passing
Equipment Induction sealing machine
1 Pass capped bottle without foil Sensor detect no foil in cap and reject the bottle No foil in cap and bottle get rejected Test was passing
2 Enter the predefined value the JAMM timer, retain the bottle for predefined time rejected will get activated Error message “ Bottle jammed at front /end” will be displayed and bottle get rejected Jammed bottle get rejected Test was passing
3 Pass capped bottle through induction cap sealer Visual inspection for proper sealing Sealing found satisfactory Test was passing
4 Leak test for capped /sealed bottle No leakage No leakage observed Test was passing
 After capping of filled bottle, it is passed through tilted cap sensor and No foil sensor to the induction sealing machine. After capping if no foil or tilted cap observed then with the help of rejection arm, bottles get rejected.
 Following in process checks were performed for rotary capper and induction sealing machine as defined frequency in BPR (By production: After every machine stoppage and By IPQA: Once in shift).
Sr.No. In process checks Observation
Rotary capping machine
1 Visual inspection of cap tightness OK
2 Torque Value (in.lb) 26.2 to 27.2
Induction sealing machine
1 Speed of conveyor (BPM) 30 bottle per minute
2 Distance between Cap & sealing head 4mm 4mm
3 Visual inspection of sealing OK
4 % power 70
5 Leak test (OK/Not OK) OK

 To ascertain the root cause, study will be performed.
Impact assessment:
 Meantime 100 % inspection of packed shipper in batch was performed and no other defect or similar defect observed. Batches packed after this incident were closely monitored and during AQL no similar defect observed.

SAP batch number of cap Used in finished product batch number AQL observation
0000067107 03118284 No unsealed bottle observation during AQL. AQL inspection passed.
03118285 No unsealed bottle observation during AQL. AQL inspection passed.
03118286 No unsealed bottle observation during AQL. AQL inspection passed.
03118287 Batch under investigation. 100 % inspection of packed shipper was done( shipper number 01to 104 ) and remaining shipper were packed with online manual inspection of bottles before labelling (shipper number 105 to 151)
000067108 03118284 No unsealed bottle observation during AQL. AQL inspection passed.
03118288 No unsealed bottle observation during AQL. AQL inspection passed.

 100 % inspection of packed bottle of batch under investigation (shipper number 01 to 104) and after that bottle were checked online (shipper number 105 to 151) and no unsealed bottle observed. Hence no risk identified.
 Further protocol based study to be performed to ascertain the root cause/most probable cause.


(YOGESH NARKHEDE) #5

Annexure III
Investigation report for I/QA/18/019
Page 1 of 2
Purpose:
Purpose of this investigation is to identify the root cause and to determine appropriate corrective and preventive actions for the missing of the MLT stamp.
Scope:
This is applicable to and not limited to
Product name : Duloxetine DR Capsules 60 mg
Batch number : 00918004
Mfg. Date : Jun.2018
Exp. Date : May 2020
Background:
Duloxetine DR Capsules 60 mg is manufactured at Inventia Healthcare Ltd. for USA market for Heritage client. The product having Mandatory microbial testing as specification part. Batch record is issued against the requirement raised by PPIC team. Issuance is carried out as requirement against verification of MLT list, and check point given in SOP CQ/024. Batch no. 00918004 was issued on 4/Jul/2018. Batch issue to production and at time of packing IPQA person withdraw the sample against batch record. At the time of issuance and verification of BPR it was missed to stamping activity on BPR for MLT test for count 30’s, 90’s and 1000’s count . Hence, sampling activity was not done during packing by IPQA. The error was noticed during QC review.
Investigation:
➢ List of Mandatory MLT provided by the Corporate quality team to issuance team. BMR issuance team track this activity manually.
➢ Issuance and Approval person is well trained in activity.
➢ Issuance person check the list and put remark on batch record that “To be sampled for MLT test” At time of issuance MLT checked was missed due to oversight error of issuance person.
➢ Issuance was done on date 04/Jul/2018 on same day batch number 00918005 for product Duloxetine DR Capsules 60 mg issued correct details.
➢ Total 48 document were issued on date 04/Jul/2018.
➢ From Jun. 2018 to 24/Aug/2018 those product having Mandatory MLT analysis as a part of release specification verify all documents for MLT remark.
Annexure III
Investigation report for I/QA/18/019
Page 2 of 2
➢ MLT analysis is performed on retention sample, from 30’s count, 90’s count and 1000 count 25 capsules withdrawn from respective count.
➢ MLT analysis is started on date 21/Aug/2018 and result of 3 day for TAMC and TYMC found nil for all count.
➢ At time of manufacturing of pellets all environmental condition meets as per batch record requirement. Common pellets for duloxetine delayed release capsule distribute in batch number Duloxetine DR capsule USP 20 mg batch number 00718001 packed in 60’s count and MLT result of same batch is complied hence no risk is anticipated.
Root cause category:
Oversight at time of issuance of batch packing record due to load of issuance : Man/People
Risk Analysis:
Other document issued on same date was issued with correct details hence no risk to document is anticipated. For MLT analysis sample is taken from retention sample and batch will distribute after the MLT result. Common pellets used for batch 00918004 was also used in Duloxetine DR capsule USP 20 mg batch number 00718001 MLT analysis result found satisfactory. Third day MLT result found Nil hence no risk to product and patient is anticipated.
Corrective Action:

  1. MLT analysis sample was withdrawn from retention sample 25 capsules from each count and issued to microbiology department for MLT analysis.
  2. Reference of incident is mentioned in batch record.
  3. Batch can be released only based on analytical results (without MLT)
  4. After sharing results of MLT batch will be distributed.
    Preventive Actions:
    Change management shall be initiate for incorporation of sampling activity in batch packing record for the product which having MLT test in release specification (Mandatory MLT for each batch).
    Prepared By:

(YOGESH NARKHEDE) #6

Annexure - III
Investigation Report Format I/PR/18/249
Purpose:
Purpose of this investigation is to identify the root cause and to determine appropriate corrective
and preventive actions for observed bottle with illegible overprinting during AQL inspection of
shipper number 01. On further verification, same bottle was observed in unsealed condition.
Scope:
This document is applicable to product Lansoprazole Delayed Release Capsules USP 15 mg
Batch numbers: A0IOR005
Pack size: 30 capsules in bottle pack
Mfg. date: Oct.2018
Exp. date: Sep.2020
Batch size: 24.75 kg ~ 150000 capsules
Background:
Product Lansoprazole Delayed release capsules 15 Batch numbers A0IOR005 was manufactured
for USA market Client: Life star pharma LLC
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 caps were used.
Bottles were cleaned in bottle unscrambler machine with air pressure 5 to 6 kg/cm2. Capsules were
filled as defined count in BPR i.e. 30 capsules per bottle and then one canister of 1 g was inserted
in bottle with help of canister inserter machine. Filled bottles were capped with the help of rotary
capping machine. After capping, these filled & capped bottles were passed through induction
machine to seal the bottles as per defined parameters in BPR.
As per procedure, during packing activity of batch no. A0IOR005 on line AQL was performed.
While performing on line AQL, one bottle with illegible overprinting in shipper number 01 and
inner box number 03. On further verification of same bottle, it was observed in unsealed condition.
Speed of 30 bottle per min with 90 % power & distance between sealing head and cap was kept
4mm as per mention in BPR.
Illegible overprinting observation was recorded first time and in the batch under investigation.
Whereas improper sealing or unsealed bottle observation was recorded earlier (incident number
I/PR/18/086) for batch number A0IOR001, A0IOR002, A0IOR003,wherein inspection of cap for
wrinkle observation was recommended and same has been followed in batch under investigation.
This report aims to identify root cause and propose actions for the observed bottle with illegible
overprinting and unsealed bottle in batch under investigation and to suggest suitable corrective and
preventive action.
SOP Ref. No. : CQ/003 Page 2 of 8
Format No.: CQ/003/F-03
Physical evaluation observed sample:

  1. On physical verification of bottle it was confirmed that initially there was overprinting and
    same was illegible. For investigation purpose overprinting matter was rubbed and observed that
    it was completely removed. However same observation was verified with other bottles which
    were under packing and no similar observation recorded. Investigation is extended to secondary
    packing activity.
  2. Same bottle was opened for correctness of sealing condition and observed bottle was unsealed
    condition. Hence this investigation extended to primary packing activity.
    Photograph of bottle:
    Bottle with illegible overprinting
    After rubbing observation.
    Unsealed bottle observation
    Investigation:
    Ishikawa (Fish bone diagram) was drawn come to investigation:
    SOP Ref. No. : CQ/003 Page 3 of 8
    Format No.: CQ/003/F-03
    Training Qualification
    Machine setting Temperature /RH Preventive /Breakdown
    Capping machine setting parameter
    Lack of knowledge Induction sealing setting parameter
    Overprinting machine for label
    Cap & bottle %Power, Distance and speed Induction sealing Parameter
    Label Torque capping machine setting
    Varnished area of overprinting Rejection handling
    Ribbon quality of printer Bottle label checking
    Bottle with illegible
    overprinting and
    unsealed condition
    Man Machine &
    Measurement
    Environment
    Material Method
    Passing of Set
    up bottle
    Rubbing to
    overprinted matter
    SOP Ref. No. : CQ/003 Page 4 of 8
    Format No.: CQ/003/F-03
  3. Investigation related to Method (Bulk packing process):
    Initial machine setting of packing line was done as per below mentioned parameters
    Sr.No. Machine Standard parameter Actual observation
    1 Bottle unscrambler machine Distance between deionizing
    and bottle mouth
    =4 mm
    4 mm
    Speed (bottle /min) 8
    2 Canister inserted machine One number of 1 g
    molecular sieve canister
    1
    3 Multi-channel tablet &
    capsule counting machine
    No of counts per bottles :
    30
    30
    4 Rotary capping machine Torque =To be validated
    and finalized after
    validation batches
    26.2 to 26.8
    5 Induction sealing machine Power (% ):90 % 90
    Speed of conveyor : 30
    bottles per minute
    30
    Distance between Cap
    and sealing head :4 mm
    4
    As per BPR instruction, required challenges for bottle unscrambler and air cleaner
    machine, Canister insertion machine for count verification was done. Electronic multichannel
    tablet and capsule counting machine was challenged for in feed conveyor, counting
    sensor, two overlapped capsules through counting sensor and for predefined count. Rotary
    capping machine was challenged for without cap, without foil, tilted cap rejection and
    found satisfactory.
    Induction cap sealer machine was challenged for no foil in cap, jam timer and leak test
    verification were done and all challenges were found satisfactory.
    After induction sealing activity, bottles were labelled, outserter was affixed on top of bottle
    and finally such labelled and sealed 12 bottles were packed in one inner carton and then
    such 12 inner box were packed in shipper.
    Secondary packing machine (Labeling machine, leaflet outserter machine, 360 degree
    system, bulk 2D machine) were set as per respective machine setup SOP and challenge
    tests were performed as per instructions mentioned on BPR and found satisfactory.
    AQL check were performed by quality assurance as a part of procedure and during AQL
    inspection, one bottle label was observed with illegible overprinting in shipper no.01. Cap
    of this bottle was opened and observed unsealed bottle. Immediately, batch packing activity
    stopped.
    Though there is observation of unsealed bottle and illegible overprinting on label during
    inspection, all challenges and in process parameters were found satisfactory.
    Secondary packing activity was initiated on 21/Nov/2018 from 23:14 to 23:24 Hrs. After
    overprinting proof checking of bottle label, 3 ply shipper label and 5 ply shipper label.03
    bottles were checked at every machine i.e. at labelling machine, outserter machine, 3 ply
    shipper packing.
    SOP Ref. No. : CQ/003 Page 5 of 8
    Format No.: CQ/003/F-03
    Bottle labels were verified for printed code of sticker label i.e. ECA0TLIOOUS70902 and
    over coding print quality , over coding details, Primary GTIN number i. e
    .00370756806301. Literature code and 3 ply shipper (inner box) were verified for bottle
    packed in inner box, NDC label quality, over coding details, Intermediate GTIN No.Then
    it was packed in shipper.
    Batch packing activity of batch under investigation was initiated on countec bulk packing
    line on 21/Nov/2018 from 22:00 Hrs to 22:40 Hrs. Till time 04 inner box were packed.
    Again on 22/Nov/2018, batch packing activity was started at 03:51 to 05:28Hrs.Remaining
    shipper no. 01 was completed and till 05: 28 Hrs, 13 shippers were packed.
    Serialization relationship report was reviewed for all packed shippers. In shipper number
    01& inner box number 03, as per serialization relationship report, Serial number
    29022654520022 was overprinted on label along with 2D and human readable matter
    of unsealed bottle. This 2D code and human readable overprinted matter was verified
    by camera system.
    As a part of investigation, on review of packing process and interaction with concerned
    technician, it was confirmed that two person were allocated for bottle inspection and may
    be during manual filling of bottle in inner box, overprinted matter on label may get
    slightly erase during handling. As a part of investigation when it was rubbed it was
    completely erased.
    Investigation with respect to unsealed bottle:
    After rotary capping, capped bottles were passed through induction sealing machine for
    sealing activity.
    On physical verification of bottle it was confirmed that there was no observation of
    partially sealing or evidence of bottle passed through the induction sealer. On interaction
    with AQL person it was confirmed that for the observed bottle was not opened easily as
    others and it may be because of tilted cap.
    Technician has performed challenge test for bottle with tilted cap and it should be rejected
    by capping machine. On interaction of concerned technician it was confirmed that due to
    lack of attentiveness of technician, this bottle was transferred to secondary packing area
    instead of destruction. This bottle might have generated during initial machine setting and
    challenge test.
  4. Investigation related to material:
    Below mentioned packing material were issued and used for packing activity. All these
    Materials were sampled and tested by QC prior release and only approved material were
    used for packing activity.
    Sr.
    No.
    Material
    name
    SAP
    code
    Batch
    number
    A.R.No. Vendor
    name
    Required
    quantity
    Issued
    quantity
    1 HDPE bottles
    60 cc with 33
    mm neck-
    DMF grade
    2000996 00000667
    67
    10000254
    782
    Shriji
    polymer
    5001 212x1
    00000681
    52
    10000263
    581
    750x7
    Total
    =5462
    SOP Ref. No. : CQ/003 Page 6 of 8
    Format No.: CQ/003/F-03
    Sr.
    No.
    Material
    name
    SAP
    code
    Batch
    number
    A.R.No. Vendor
    name
    Required
    quantity
    Issued
    quantity
    2 CR Cap
    33mm with
    induction seal
    –DMF grade
    2001305 00000677
    14
    10000260
    306
    Shriji
    polymer
    5001 1700x3=
    5100
    3 1 g molecular
    sieve canister
    –DMF grade
    2000974 00000640
    08
    10000023
    8744
    Clarient
    plastics
    and
    coating
    USA
    5001 4000x1
    3357x1
    =Total
    7357
    4 Sticker Label
    (30 capsules )
    for
    Lansoprazole
    Delayed
    released
    capsules USP
    15 mg
    2007165 00000676
    97
    10000260
    153
    HUHTA
    MAKI
    PPL
    LTD.
    5001 3990
    +1990=5
    980
  5. 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 status
    1 Bottle unscrambler machine PR297 15/Nov/2017
    2 Multi-channel Tablet and capsule
    counting machine
    PR299 15/Nov/2017
    3 Canister inserter machine PR298 15/Nov/2017
    4 Rotary Capping machine PR301 15/Nov/2017
    5 Induction sealing machine PR302 15/Nov/2017
  6. Investigation related to personnel:
    Involved operator and packing /IPQA officer during packing are trained and competent
    to perform packing activity.
    Activity Name of person involved Availability of training
    Bottle line officer
    secondary
    Ganesh Desale Available
    Bottle checking Ankush Kadaw Available
    Ketan Shelke Available
    Bottle line officer primary Avinash Desai Available
    SOP Ref. No. : CQ/003 Page 7 of 8
    Format No.: CQ/003/F-03
    Root Cause:
    Root cause for illegible overprinting:
    As per serialization relationship report, Serial number 29022654520022 was overprinted
    on label along with 2D and human readable matter of unsealed bottle. This 2D code and
    human readable overprinted matter was verified by camera system. During manual filling
    of bottle in inner box, overprinted matter on label may get slightly erase during handling.
    During investigation of overprinted matter quality, all overprinted matter got erase due to
    rubbing on overprinted matter. Other bottles overprinting quality of label was checked from
    same shipper and no discrepancy observed. There may be varnished quality issue of that
    particular label which leads to removal of overprinted matter on label.
    Root cause for unsealed bottle:
    During investigation, it is revealed that during challenge (bottle with tilted cap) of rotary
    capping machine should be rejected. Technician has performed challenge and tilt capped
    bottle was rejected by machine. However, due to lack of attentiveness of technician, this
    bottle may be transferred to secondary packing area instead of destruction.
    Corrective Action:
  7. All the bottles from shipper number 1 to 13 were checked for sealing and overprinted
    matter quality on label. No discrepancy observed.
  8. Persons involved in bottle inspection were made aware about the observed defect in
    packed bottle. Further no similar observation recorded during packing activity.
    Risk Analysis:
    Observed bottle with illegible overprinting was removed and existing packed shipper (01
    to 13) were verified and no similar observation recorded. Involved persons were made
    aware about the noted observation and no similar observation recorded thereafter.
    Overprinting details get erased on extensive rubbing of overprinted matter. During
    transportation and dispensing, overprinted batch details may not get erased unless and
    otherwise it got extensive rubbed during handling. It may not get erased during
    transportation and dispensing. Hence no risk to product identity.
    Unsealed bottle identified during AQL inspection and after inspection of existing packed
    13 shipper there were no similar observation recorded. Bottle label is having instruction as
    “Do not accept if seal over bottle opening is broken or missing”. Hence no risk identified
    with respect to product safety for patient.
    SOP Ref. No. : CQ/003 Page 8 of 8
    Format No.: CQ/003/F-03
    Preventive Action:
  9. All machine setup and initial checks bottles to be debottled before start of batch
    packing activity and packing machines/ area to be verified by production officer for
    absence for machine setup and initial checks bottles. It is to be recorded in batch
    packing record.
  10. Improper overprinting quality of label was taken with OEM of printing machine
    and to be check with label manufacture for identification of cause.
    Prepared

(YOGESH NARKHEDE) #7

Annexure - III

Investigation Report for I/PR/18/248

Purpose:

Purpose of this investigation is to investigate the root cause and to determine appropriate corrective and preventive actions reduction in speed during compression of Glimy M 2 Forte Tablet at Korsch XL 400 compression machine.

Scope:

The Scope of this report is applicable on:-

  • Product Name: Glimy M 2 Forte Tablet
  • Generic Name: Metformin Hydrochloride Prolonged 1000mg and Glimepiride 2 mg Tablets IP.
  • B. No.: A01631812
  • Batch Size: 515000 Tablets.
  • Mfg. Date: Nov.2018
  • Exp. Date: Oct.2020
  • Manufactured by: Inventia Healthcare Ltd.
  • Marketed by: Dr. Reddy’s Laboratories

Background

To overcome the problem of layer separation actual speed of compression machine reduced in this batch, details of batch is given below

Glimy M2 Forte Tablets is a bi-layer tablet with the composition of

  • White layer - Metformin hydrochloride SR Granules 78.43% W/W
  • Color part - Glimepiride granules 0.889% w/w.

Various stages involved in the manufacturing process of Glimy M 2 Forte Tablet likewise dry mixing, wet granulation, drying & lubrication. After Lubrication batch transferred to compression stage.

In above said batch to get tablets free from layer separation at friability, compression machine speed was reduced to 10 RPM from standard limit mentioned in BMR as 30 RPM to 50 RPM & hardness limit is 12 Kp to 40 Kp.

The compression was done on Korsch XL 400 compression machine.

Investigation:

Granulation parameters found well within limit ( Refer attached Granulation parameter Data).

The compression activity was started on 17/Nov./2018 on Korsch XL 400 machine (PR 040)

  • During Friability test at initial setting of product at compression stage, layer separation in some tablets were observed at compression speed 30 RPM.
  • Hence to get tablets free from layer separation, compression machine speed was reduced to 25 RPM from 30 rpm against the standard speed 30 to 50RPM. Layer separation was also observed at 25rpm, layer of tablet gets separated during friability test.
  • To overcome this problem, again machine speed was reduced to 20 RPM. At 20 RPM layer separation observed again in continuation.
  • Then again machine speed reduced to 15RPM and same defect observed so machine Speed reduced to 10 RPM.
  • At 10 RPM all compression parameters of tablets observed well within BMR limits.
  • Hence after satisfactory result of in-process checks batch was continued at the speed of 10 RPM.

Above said batch was compressed with machine speed at 10 RPM. As all the parameter was well within specified limit at reduce compression speed no impact on quality product is anticipated. 200gm sample of metformin hydrochloride SR granules 78.43% w/w granules and 200gm sample of Glimepiride granules 0.889% w/w was withdrawn for physical property test

Final product will be released only after complying finished product specification.

Investigation related to material.

Used material taken for Granulation activity is from approved source.

Angle of repose ( Metformin Granules : 38 Degree and Glimepiride granules : 34 degree) and hausner ratio ( Metformin Granules : 1.143 and Glimepiride granules : 1.074) observed satisfactory.

Investigation related to equipment and measurement.

Details of compression machine used in compression were as follows:

Sr. No. Equipment name Equipment ID Qualification status
1. Korsch XL400 PR040 Qualified

Preventive maintenance & breakdown of equipment

Preventive maintenance and qualification were carried out as defined schedule and no any abnormal observation was noted.

Not any breakdown observed during manufacturing.

Investigation related personnel.

Involved technician and officers were trained and competent to perform the compression activity.

Investigation related to Environment.

Environmental condition Temperature & humidity maintained during manufacturing activity were as defined in BMR.

Root Cause:

Probable root cause may be variation in fines distribution throughout granules, lead to generation of capping defect. To avoid capping problem of the tablets 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 BMR limit. Tablets compressed during initial setting was rejected and sent for destruction.
  • Batch will be released only after complying finished product specification.

Risk Analysis:

It has been cleared that there is not any impact on tablet quality. After speed reduction of tablet compression machine, quality of tablet improved & capping problem resolved. All in-process parameters except machine speed found well within the specified limit. All compression parameter found complying with specification. Hence there is no impact on the quality of product.

Preventive Action:

Protocol base study shall be performed for next five batches from granulation to compression stage and based on the evaluation further action plan shall be decided.


(YOGESH NARKHEDE) #8

Annexure III
Investigation Report to I/PR/18/247
Purpose:
Purpose of this annexure is to investigate the cause of compression of Panfor SR 500 at 18 RPM on 51
station tablet compression machine instead of 25-30 RPM.
Scope:
The Scope of this annexure is applicable to Panfor SR 500
Generic Name: Metformin Hydrochloride Sustained Release Tablets 500mg.
B.No. PAF01433, PAF01434 & PAF01435
B.Size: 1030000 Tabs.
Mfg. date- Nov.2018
EXP. date- Oct.2021
Marketed by: Mega life sciences.
Background
Panfor SR 500 is single layer product, with composition of Metformin hydrochloride SR granules 59.88
w/w. Compression of Panfor SR 500, B.No. PAF01433, PAF01434 and PAF01435 done on 51 station
tablet compression machine, during initial setting desired hardness was not achieved (i.e.NLT 10.0 Kp),
hence speed was reduced to 18 RPM against standard speed 25 to 30 RPM.
Investigation: For B.no. PAF01433

  1. Panfor SR 500 B.No. PAF01433 is planned for compression on 51 station tablet compression
    machine (on 23/Nov/2018). During initial setting machine RPM was kept 25 RPM, while at
    this RPM concern person was found that specified hardness is not achieved for some tablets
    i.e. NLT 10.0 Kp.
  2. Panfor SR 500 B.No. PAF01433 is single layer tablet with the composition of Metformin
    hydrochloride SR granules 59.88 % w/w. Stages involves in manufacturing process are sifting,
    granulation, drying, sizing , lubrication and compression.
  3. During initial setting at compression stage, desired hardness i.e. NLT 10 Kp was not achieved
    at compression machine speed 25 RPM.
  4. Hence compression machine speed was reduced to 18 RPM from 25 RPM against the standard
    speed as specified in BMR 25 to 30 RPM. At 18 RPM speed all parameters was found well
    within the specified limit.
  5. Granules of Metformin hydrochloride SR granules 59.88 % w/w from B.No.PAF01433 was
    used. Details of granulation stage are as follows.
    a. LOD was 3.85 % (lot I), 4.07 % (Lot II) against the standard limit 3.5-4.5 % W/W.
    b. Co mill speed was 500 RPM (Lot I) and 500 RPM (Lot II)
    c. Amperage reading 52.5 (Lot I) and 52.7 (Lot II).
    d. Drying time 55 min (Lot I) and 55 min (Lot II).
    Investigation: For B.no. PAF01434
  6. Panfor SR 500 B.No. PAF01434 is planned for compression on 51 station tablet compression
    machine (on 23/Nov/2018). During initial setting machine RPM was kept 25 RPM, while at this
    RPM concern person was found that specified hardness is not achieved for some tablets i.e. NLT
    10.0 Kp.
  7. Panfor SR 500 B.No. PAF01434 is single layer tablet with the composition of Metformin
    hydrochloride SR granules 59.88 % w/w (Material code 3000355). Stages involves in manufacturing
    process are sifting, granulation, drying, sizing, lubrication and compression.
  8. During initial setting at compression stage, desired hardness i.e. NLT 10 Kp was not achieved at
    compression machine speed 25 RPM.
    Page 2 of 2
    Format No.: CQ/003/F-03
  9. Hence compression machine speed was reduced to 18 RPM from 25 RPM against the standard speed
    as specified in BMR 25 to 30 RPM. At 18 RPM speed all parameters was found well within the
    specified limit.
  10. Granules of Metformin hydrochloride SR granules 59.88 % w/w from B.No.PAF01434 was used.
    Details of granulation stage are as follows.
    a. LOD was 3.95 % (lot I), 4.04 % (Lot II) against the standard limit 3.5-4.5 % W/W.
    b. Co mill speed was 500 RPM (Lot I) and 500 RPM (Lot II)
    c. Amperage reading 53.0 (Lot I) and 53.2 (Lot II).
    d. Drying time 57 min (Lot I) and 57 min (Lot II).
    Investigation: For B.no. PAF01435
  11. During initial setting at compression stage, desired hardness i.e. NLT 10 Kp was not achieved at
    compression machine speed 25 RPM.
  12. Hence compression machine speed was reduced to 18 RPM from 25 RPM against the standard speed
    as specified in BMR 25 to 30 RPM. At 18 RPM speed all parameters was found well within the
    specified limit.
  13. Granules of Metformin hydrochloride SR granules 59.88 % w/w from B.No.PAF01435 was used.
    Details of granulation stage are as follows.
    a. LOD was 3.77 % (lot I), 3.80 % (Lot II) against the standard limit 3.5-4.5 % W/W.
    b. Co mill speed was 500 RPM (Lot I) and 500 RPM (Lot II)
    c. Amperage reading 52.0 (Lot I) and 53.7 (Lot II).
    d. Drying time 57 min (Lot I) and 58 min (Lot II).
    Root Cause:
    Probable root cause may be variation in fines distribution throughout granules, lead to generation of
    capping defect. To avoid capping problem of the tablets 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:
    Protocol base study shall be performed for next five batches from granulation to compression stage
    and based on the evaluation further action plan shall be decided

(YOGESH NARKHEDE) #9

Annexure - III
Investigation Report for I/PR/18/243
Purpose:
Purpose of this investigation is to identify the root cause and to determine appropriate corrective and preventive actions for crack observed on dies during compression.
Scope:
The Scope of this investigation report is applicable to
Product: Metformin hydrochloride extended release tablets USP 500
Batch No.: 03118357
Batch Size : 925000 Tablets
Mfg. Date : Nov.2018
Exp. Date : Oct. 2020
Stage :- Compression
Market – U.S.A
Background:
Punch set 18.0x9.0mm capsule shape, standard concave punches with bevelled edges, Box number 123 were used in compression activity of product Metformin hydrochloride extended release tablets USP 500 mg. These punches were used on 53 station compression machine.
After completion of compression activity during inspection on 13/Nov/2018, hair line cracks observed on 39 dies.
➢ Description of Die & Punches: -
➢ Punch set -18.00 mm X 9.00 mm capsule shape, standard concave punches with bevel edges supplied by KTT Pharmatech .
New punch set: - Box no. 123- in this 60 sets of dies & punches received on 04/Nov/2018.
o Manufacturer: KTT Pharmatech
o Dimension: 18.0 x 9.0mm (17.970x8.970 +0.000/-0.020)
o Shape: Capsule, Bevel, Concave
o Tooling Type: ‘D’ Type
o Punches steel type: - S7 & OHNS
o Dies steel type D3- ASTM A681
➢ Description of machine: -
Box number 123 was used on 53 station tablet compression machine PR398.
SOP Ref. No.: CQ/003 Page 2 of 9
Format No.: CQ/003/F-03
Sr. No.
Equipment name
Equipment ID
Station
1
SAJONG- VENTIX
P720D
PR398
53 Station
Details of dies observed with hair line crack: -
➢ In primary investigation it had been cleared that 39 dies found with minor hair line crack. Details as mentioned below:
Box No.
Crack observation date
Serial number of dies found with hair line crack in observation
Total number of dies found with hair line crack in observation
123
13/Nov/2018
01,02,03,04,05,06,07,08,09,11,12,13,14,16,18,19,21,22,23,25,26,27,28,30,31,32,33,36,37,38,39,40,42,43, 47,48,49,50,52
39
Actual photograph of die after hair line crack:
SOP Ref. No.: CQ/003 Page 3 of 9
Format No.: CQ/003/F-03
Box no. 123– photograph of die with minor hair line crack
SOP Ref. No.: CQ/003 Page 4 of 9
Format No.: CQ/003/F-03
Investigation:
Ishikawa (Fish bone diagram) was drawn come to investigation
Training Qualification
Machine setting Preventive /Breakdown
Maintenance
Lack of knowledge
Temperature /RH Compression machine parameter
In area
Compression force
Process
Parameter
MOC of dies
Hair line crack observed on dies
Man
Machine & Measurement
Material
Method
Environment
SOP Ref. No.: CQ/003 Page 5 of 9
Format No.: CQ/003/F-03
➢ Investigation related to Method
In process checks recording: Performed in process checks during compression activity of batch under investigation and details are mentioned below.
Product name: - Metformin hydrochloride ER tablets USP 500 mg

  1. Loss on drying: -
    Batch No.
    LOD- Lot No. 1
    LOD- Lot No. 2
    03118357
    2.95 % (limit 2.5-3.2)
    3.10% (limit 2.5-3.2)
  2. Hardness & Friability :-
    Sr. No.
    Batch No.
    Observation
    Hardness Limits: - 13.0 - 23.0 Kp
    Friability Limit: - NMT 1.0 % w/w
    MIN.
    MAX.
    MIN.
    MAX.

03118357
13.7
19.7
0.010
0.302
3. Manufacturing & packing yield:-
Sr. No.
Batch No.
Mfg.
Packing
% Actual yield
Limit:
NLT 98%
% Theoretical yield Limit:
NLT 95%
% Actual yield
Limit:
NLT 97%
% Theoretical yield Limit:
NLT 94%
1.
03118357
99.03
99.58
99.77
98.27
Serial No.
In process parameters
Observation
01
LOD
Within limit as per written in BMR
02
Hardness
Within limit as per written in BMR
03
Friability
Within limit as per written in BMR
04
Machine speed
25-30 rpm (limit 20-65 rpm)
05
Physical appearance of tablet
Good
06
Manufacturing & packing yield
Within limit
Evaluation: - In process checks recorded during compression activity of Metformin hydrochloride ER tablets USP 500 mg batch number 03118357 were found complying with predetermined ranges specified in BMR/BPR.
SOP Ref. No.: CQ/003 Page 6 of 9
Format No.: CQ/003/F-03
Investigation related to machine and measurement:
Used equipment SAJONG- VENTIX P720D for compression of said batches of metformin are already in qualified status.
Preventive maintenance of equipment
Preventive maintenance and qualification were carried out as per defined schedule and no any abnormal observation was noted.
Equipment parameters setting was done as defined in respective batch record.
Sr. No.
Equipment name
Equipment ID
Preventive maintenance done on
Due on
1
SAJONG- VENTIX
P720D
PR398
25/Sep/2018
Dec2018
Setting parameters of compression machine: - In primary investigation machine setting parameters found within limit.
Pressure in KN of set compression force during compression activity of said batch number as mentioned below;
Batch number
Date
Time
Average main pressure (compaction force) KN
Maximum main pressure (compaction force) KN
Minimum main pressure (compaction force) KN
03118357
12/NOV/2018
21:57:21
58.42
61.83
55.29
03118357
12/NOV/2018
21:41:25
58.47
62.11
55.21
03118357
12/NOV/2018
21:29:26
58.87
62.08
54.16
03118357
12/NOV/2018
20:31:42
59.13
62.90
54.58
03118357
12/NOV/2018
20:05:58
58.32
62.43
54.31
03118357
12/NOV/2018
19:27:36
58.12
63.07
54.92
03118357
12/NOV/2018
18:44:23
57.39
61.35
54.84
03118357
12/NOV/2018
17:25:55
57.18
61.46
53.17
03118357
12/NOV/2018
17:11:25
57.26
61.53
53.97
Required compression force during compression activity of batch number 03118357 was within limit.
Evaluation:
➢ Interrogation with concerned operator was done to check the machine set up and punches and dies setting activity. It was confirmed that punches and dies setting was done as per procedure and there was no abnormal observation with respect to punches and dies setting.
SOP Ref. No.: CQ/003 Page 7 of 9
Format No.: CQ/003/F-03
➢ Set compression force during compression activity of batch under investigation was higher side to standard but within limit. Compression parameter of product found complying with specification. Hence further investigation extended to used punches and dies material.
Investigation related to Material (MOC of dies):
➢ Description of Die & Punches: -Punch set 18.00 mm X 9.00 mm capsule shape, standard concave punches with bevelled edges supplied by KTT Pharmatech.
➢ Punch set: - Box no. 123- in this 60 sets of dies & punches received on 04/Nov/2018.
➢ Observed hair line crack problem share with vendor: KTT Pharmatech. Vendor is investigating this matter also for problem related to MOC.
➢ Vendor Inspection report of punches and dies checked and observed that that steel used for die manufacturing was D3 steel.
➢ MOC results: Sample send for testing results will be attached after receiving report from testing laboratory.
Evaluation:
Evaluation will be done after receiving testing report of MOC (material of construction) from external testing agency. If any problem with MOC found, then action should be taken accordingly.
Investigation related to personnel:
➢ Involved operator and officer were properly trained & sufficient experience to change over or setting compression machine.
Investigation related to environment:
➢ Environmental condition maintained during compression activity, was within limit as defined in BMR.
Root Cause:

  1. Probable reason for hair line crack observation may be material of construction of dies.
    Corrective Action:
  2. 100 % inspection tablets go through metal detector. So, there was not any chance to go metal piece with in the tablet.
  3. 100 % inspection of cracks or any other unwanted line on tablet of all batches done on enclony inspection machine.
    SOP Ref. No.: CQ/003 Page 8 of 9
    Format No.: CQ/003/F-03
    Risk Analysis:
    Impact of this observation may be on the physical parameters of tablet and chance of compression of small metal piece with granules is possible. It may lead to market complaint. However all compressed tablets are passed through metal detector, hence tablets contaminated with any metal particle will be rejected. All process parameters maintained for compression machine were observed as per BMR instructions, hence no risk is anticipated.
    Inspection details through Enclony :- after evaluation of report of Enclony it has been cleared that there was no any kind of impact seen throughout the batch.
    Product name
    Batch number
    Date /Time
    Yield
    Metformin hydrochloride ER tablets USP 500 mg
    03118357
    Start at 13/NOV/2018 10:46 hrs
    End at 14/NOV/2018 03:40 hrs
    99.22 %
    Detailed investigation of friability & hardness of batches likely to be affected given below: -
    Sr. No. Batch No. Observation Hardness Limits: - 13.0 - 23.0 KP Friability Limit: - NMT 1.0 % w/w LHS (Lower-Upper) RHS(Lower-Upper) LHS RHS.

03118357
14.7- 17.0
14.1- 19.0
0.267
0.279
2.
03118357
14.9- 17.2
13.7- 16.1
0.150
0.302
3.
03118357
14.9- 17.1
13.9- 16.4
0.053
0.238
4.
03118357
15.0- 17.6
14.5- 16.1
0.010
0.021
5.
03118357
14.9- 17.1
14.0- 16.4
0.064
0.064
6.
03118357
14.0- 17.8
13.9- 17.4
0.107
0.227
7.
03118357
15.3- 17.0
15.4- 17.2
0.064
0.075
8.
03118357
16.0- 19.5
14.7- 19.7
0.097
0.118
9.
03118357
16.6- 18.6
16.0- 18.7
0.075
0.086
Evaluation: -
After evaluation of batch, it has been found that in process parameters were within predetermined specification limits of BMR. Friability, hardness, yield of manufacturing, yield of packing were within limit. Hence there was no impact on the quality of batches which was manufactured during this period. As per standard practice, 100 % inspection tablets passed through metal detector for detection of metal, but results found satisfactory. For detection of
SOP Ref. No.: CQ/003 Page 9 of 9
Format No.: CQ/003/F-03
cracks, spots & visual defects, 100 % inspection of tablet of all above said batches done on Enclony inspection machine and result found within predetermined limits.
Preventive Action:
➢ After receiving MOC report of dies from testing laboratory, if require we will re-evaluate action plan.
Prepared By: Reviewed By: Approved By


(YOGESH NARKHEDE) #10

Annexure - III
Investigation Report for I/PR/18/242
Purpose:
Purpose of this investigation is to investigate the root cause and to determine appropriate corrective and preventive actions reduction in speed during compression of Cetapin V 0.3 mg Tablet at Korsch XL 400 compression machine.
Scope:
The Scope of this report is applicable to:-
o Product Name: Cetapin V 0.3 mg
o Generic Name: Metformin Hydrochloride SR 500 mg and Voglibose 0.3 mg Tablets.
o B. No.: 0718011
o Batch Size: 515000 Tablet
o Mfg. Date: Nov. 2018
o Exp. Date: Oct. 2020
o Manufactured by: Inventia Healthcare Ltd.
o Marketed by: Sanofi India Ltd.
Background
To overcome the problem of layer separation actual speed of compression machine reduced in this batch, details of batch is given below
Cetapin V 0.3 mg Tablets is a bi-layer tablet with the composition of
o White layer - Metformin hydrochloride SR Granules 59.88 % W/W
o Violet layer – Voglibose granules 0.14 % w/w.
Metformin hydrochloride SR Granules 59.88 % W/W manufacturing process involves sifting, dry mixing and wet granulation in FBE 1300 L, Drying in FBE 1300 L & lubrication in octagonal blender. After lubrication batch transferred to compression stage.
Voglibose granules 0.14 % w/w. manufacturing process involves sifting, dry mixing and wet granulation in RMG ( 600 L) followed by drying in FBE and lubrication in Cage blender (500 L). After Lubrication batch transferred to compression stage.
In above said batch to get tablets free from capping defect and low hardness, compression machine speed was reduced to 20 RPM from standard limit mentioned in BMR as 35 RPM to 45 RPM. Similar type of incident was observed in Batch No. 0718009 and 0718010 wherein compression machine was 51 station (Gigapress - PR049) (Incident No. I/PR/18/161).
The compression of this batch was done on Korsch XL 400 compression machine ( PR040).
Investigation:

  1. Investigation related to Method :
    ➢ Metformin hydrochloride SR Granules 59.88 % W/W manufacturing process involves sifting, dry mixing and wet granulation in FBE 1300 L, Drying in FBE 1300 L & lubrication in octagonal blender.
    SOP Ref. No.: CQ/003 Page 2 of 3
    Format No.: CQ/003/F-03
    ➢ Voglibose granules 0.14 % w/w. manufacturing process involves sifting, dry mixing and wet granulation in RMG ( 600 L) followed by drying in FBE and lubrication in Cage blender (500 L).
    ➢ Granulation parameters found well within limit ( Refer attached Granulation parameter Data).
    ➢ The compression activity was started on 15/Nov/2018 at 22:50 hrs. on Korsch XL 400 machine (PR 040) and completed on date 16/Nov/2018 at 12:43 hrs.
    ➢ At the start of compression activity speed of compression machine was set at the standard speed of 35 RPM capping defect and low hardness (11.80 to 14.20 Kp) was observed against standard of 12.0 to 35.0 Kp
    ➢ Speed of compression machine was reduced to 30 RPM hardness observed as 11.90 to 14.10 kp), hence again speed reduced to 25 RPM, at this speed capping defect was observed and hardness observed within limit.
    ➢ Hence again speed was reduced to 20 RPM. At this speed, all compression parameters observed well within the limit, hence compression activity continued at the speed of 20 RPM.
  2. Investigation related to material.
    ➢ All the materials used in granulation were in approved state.
    ➢ 200gm sample of Metformin hydrochloride SR Granules 59.88 % W/W and 200gm sample of Voglibose granules 0.14 % w/w was withdrawn for physical property test. Observations were as follows
    Yield of the batch at compression stage observed less than limit due to rejection at initial machine setting and rejection in dust collector ( For detailed investigation refer attachment.)
  3. Investigation related to equipment and measurement.
    ➢ Details of compression machine used in compression were as follows:
    Sr. No.
    Equipment name
    Equipment ID
    Qualification status

Korsch XL400
PR040
Qualified
Angle of Repose
Hausner Ratio
Metformin hydrochloride SR Granules 59.88 % W/W
37°
1.172
Flow Property
Fair
Good
Voglibose granules 0.14 % w/w
35°
1.115
Flow Property
Good
Good
SOP Ref. No.: CQ/003 Page 3 of 3
Format No.: CQ/003/F-03
Preventive maintenance & breakdown of equipment
➢ Preventive maintenance and qualification were carried out as defined schedule and no any abnormal observation was noted. No any breakdown observed during manufacturing.
4. Investigation related personnel.
➢ Involved technician and officers were trained and competent to perform the compression activity.
5. Investigation related to Environment.
➢ Environmental condition Temperature & humidity maintained during manufacturing activity were as defined in BMR.
Root Cause:
➢ Probable root cause may be variation in fines distribution throughout granules, lead to generation of capping defect. To avoid capping problem of the tablets 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 BMR limit. Tablets compressed during initial setting was rejected and sent for destruction.
➢ Batch will be released only after complying finished product specification.
Risk Analysis:
➢ It has been cleared that there is no any impact on tablet quality. After speed reduction of tablet compression machine, quality of tablet improved & capping problem resolved. All in-process parameters except machine speed found well within the specified limit. All compression parameter found complying with specification. Hence there is no impact on the quality of product.
Preventive Action:
➢ Protocol base study shall be performed for next five batches from granulation to compression stage and based on the evaluation further action plan shall be decided.
Prepared By:


(YOGESH NARKHEDE) #11

Annexure III
Attachment-I to Investigation Report Format I/PR/18/242
Purpose:
Purpose of this annexure is to investigate the less yield observed at compression stage of Cetapin V 0.3, Batch No. 0718011.
Scope:
The Scope of this annexure is applicable for Cetapin v 0.3, Batch No. 0718011.
Background:
At compression stage during reconciliation it was observed that the % yield of the batch was observed 88.95 % against the standards yield limit NLT 90 %.
Investigation:
During compression at initial setting at speed 35 RPM of tablet compression machine, tablet hardness observed at lower side i.e. From 11.8 Kp to 14.20 Kp (Limit- 12.0 Kp to 35 Kp) also at same machine speed capping observed on tablet. To get the rid of hardness and capping issue machine speed reduced to 20 RPM. At 20 RPM all inprocesss parameter found within BMR specified limit. During initial setting due to change in machine RPM rejection of tablet generated was 10.550 kg.
Reconciliation details are as follows:-
1
Planned theoretical batch size : 540.750 kg ≈ 515000 tablets
2
Calculated theoretical yield (Kg) :536.915 kg ≈ 507952 tablets
3
Sample Quantity (a +b + c)
Kg
No
a) In process Sample
1.996
640 +1260
b) QC Sample
0.157
150 Tablets
c) Other samples during compression
200 gm Metformin
200 gm Voglibose
380 Tablets
Total (a +b + c)
2.553 Kg
2430
5
Handling Waste (d +e + f) = 56.500 kg
d) Metformin HCL SR granules left over in Kg: 24.025 kg
e) Voglibose granules Left over in kg : 0.250
f) Reject (I + ii + iii)
Sr. no.
Qty. of Tablet rejected
Kg
No.
i)
During compression
10.550 ® + 6.055 ˣ
15805
ii)
During Inspection

iii)
Other rejection
15.620 ˣ ˣ

6
Total Rejects = Step 5 + a = 58.496 kg
7
Yield in % (step 3 + Step 4) / Step 2 X 100 = 88.95 %
Range for % yield = NLT 90 %
SOP Ref. No.: CQ/003 Page 2 of 2
Format No.: CQ/003/F-03
7
Standard Yield in % {( Step 3+Step 4) / Step 1 X100 } = 87.74 %
Range for % yield = NLT 90 %
8
Reconciliation in % {(Step 3 + Step 4 + Step 5) / Step 2 X 100} = 99.55 %
®-Initial setting rejection – 10.550 kg, ˣ- AWC rejection – 6.055 kg, ˣ ˣ - Layer II dust collector rejection – 15.620 kg
Total rejection generated during compression = 58.496 kg ≈ 11.0 %.
Root Cause:
To achieved desired hardness speed was reduced at different RPM (35, 30, 25 and 20 RPM) hence more rejection were generated and same was impacted on yield.
Corrective Action:
Rejected tablets sent to solid waste destruction.
Risk Analysis:
Only 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


(YOGESH NARKHEDE) #12

Annexure - III

Investigation Report for I/PR/18/238

Purpose:

Purpose of this investigation is to investigate the root cause and to determine appropriate corrective and preventive actions reduction in speed during compression of Glyciphage G2 Tablet at Korsch XL 400 compression machine.

Scope:

The Scope of this report is applicable on:-

  • Product Name: Glyciphage G2
  • Generic Name: Metformin Hydrochloride Prolonged 500mg and Glimepiride 2 mg Tablets IP.
  • B. No.: IA18028
  • Batch Size: 1040000 Tablet
  • Mfg. Date: Nov.2018
  • Exp. Date: Apr.2021
  • Manufactured by: Inventia Healthcare Ltd.
  • Marketed by: Franco Indian Pharmaceuticals Pvt Ltd.

Background

To overcome the problem of layer separation actual speed of compression machine reduced in this batch, details of batch is given below

Glyciphage G2 Tablets is a bi-layer tablet with the composition of

  • White layer - Metformin hydrochloride SR Granules 59.88 % W/W
  • Yellow layer - Glimepiride granules 0.93 % w/w.

Metformin hydrochloride SR Granules 59.88 % W/W manufacturing process involves sifting, delumping, dry mix, and wet granulation in RMG, Drying in FBD 1300 L & lubrication in octagonal blender. After lubrication batch transferred to compression stage.

Glimepiride granules 0.93 % w/w. manufacturing process involves sifting, dry mixing and wet granulation in RMG followed by drying in FBE and lubrication in octagonal blender. After Lubrication batch transferred to compression stage.

In above said batch to get tablets free from capping defect, compression machine speed was reduced to 22 RPM from standard limit mentioned in BMR as 30 RPM to 50 RPM & hardness limit is 12 Kp to 35 Kp. This was the First incident on Korsch XL machine ( PR040) for Glyciphase G2.

The compression was done on Korsch XL 400 compression machine ( PR040).

Investigation:

Investigation related to Method :

Metformin hydrochloride SR Granules 59.88 % W/W manufacturing process involves sifting, delumping, dry mix, and wet granulation in RMG, Drying in FBD 1300 L & lubrication in octagonal blender .

Glimepiride granules 0.93 % w/w. manufacturing process involves sifting, dry mixing and wet granulation in RMG followed by drying in FBE and lubrication in octagonal blender.

Granulation parameters found well within limit ( Refer attached Granulation parameter Data).

On evaluation of compressed tablets parameters observed that hardness is on lower side as compared to batch compressed at standard speed.

The compression activity was started on 06/Nov/2018 on Korsch XL 400 machine (PR 040) and due to holiday from 07/Nov/2018 to 11/Nov/2018, activity again started on 12/Nov/2018 and completed on date 13/Nov/2018.

  • At the initial stage (Date: 06/Nov/2018 at 09:40 hrs. to 18:04 hrs.) compression machine was run at the speed of 30 RPM and no capping defect was observed.
  • At 14:20 hrs. on date 06/Nov/2018 oil spot observed on tablets ,hence machine was stopped and punch cleaning performed and after cleaning again machine was started.
  • At 18:05 hrs. Operator Mr. Pramod Botungale observed capping defect in tablet, hence compression machine was stopped and again setting of machine performed. Speed of the compression machine was reduced to 22 RPM from 30 RPM.
  • At the speed of 22 RPM all compression parameters observed well within the limit, hence compression activity continues at the same speed.
  • In the next batch No. IA18029, at the initial setting Operator Mr. Pramod Botungale observed that desired hardness ( 12 Kp to 35 Kp) was not getting achieved, hence speed of compression machine was reduced to 22 RPM and compression activity completed. At the speed of 22 RPM, all compression parameters observed within the limit.

Investigation related to material.

  • All the materials used in granulation were in approved state.

  • 200gm sample of metformin hydrochloride SR granules 78.43% w/w granules and 200gm sample of Glimepiride granules 0.889% w/w was withdrawn for physical property test. Angle of repose ( Metformin Granules : 35 Degree and Glimepiride granules : 34 degree) and hausner ratio ( Metformin Granules : 1.161 and Glimepiride granules : 1.120) observed. On evaluation of angle of repose and hausner ratio it was observed that powder flow properties observed good.

  • Investigation related to equipment and measurement.

  • Details of compression machine used in compression were as follows:

Sr. No. Equipment name Equipment ID Qualification status
1. Korsch XL400 PR040 Qualified

Preventive maintenance & breakdown of equipment

Preventive maintenance and qualification were carried out as defined schedule and no any abnormal observation was noted. No any breakdown observed during manufacturing.

  • Investigation related personnel.

  • Involved technician and officers were trained and competent to perform the compression activity.

  • Investigation related to Environment.

  • Environmental condition Temperature & humidity maintained during manufacturing activity were as defined in BMR.

Root Cause:

Probable root cause may be variation in fines distribution throughout granules, lead to generation of capping defect. To avoid capping problem of the tablets 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 BMR limit. Tablets compressed during initial setting was rejected and sent for destruction.
  • Batch will be released only after complying finished product specification.

Risk Analysis:

It has been cleared that there is no any impact on tablet quality. After speed reduction of tablet compression machine, quality of tablet improved & capping problem resolved. All in-process parameters except machine speed found well within the specified limit. All compression parameter found complying with specification. Hence there is no impact on the quality of product.

Preventive Action:

Protocol base study shall be performed for next five batches from granulation to compression stage and based on the evaluation further action plan shall be decided.


(YOGESH NARKHEDE) #13

Annexure - III
Investigation Report for I/PR/18/231

Purpose:
Purpose of this investigation is to investigate the root cause and to determine appropriate corrective and preventive actions for observed capping during compression of Glyciphage PG2 Tablet on 51 Station compression machine (PR049).

Scope:
The Scope of this report is applicable to:-
o Product Name: Glyciphage PG2
o Generic Name: Metformin hydrochloride SR 500 mg, Pioglitazone Hydrochloride 15 mg and Glimepiride 2 mg Tablets
o B. No.: IA18013
o Batch Size: 510000 Tablets.
o Mfg. Date: Oct. 2018
o Exp. Date: Sep. 2020
o Manufactured by: Inventia Healthcare Ltd.
o Marketed by: Franco Indian Pharmaceuticals Pvt. Ltd.

Background
Glyciphage PG2 Tablets is a bi-layer tablet with the composition of
o White layer - Metformin hydrochloride SR Granules 59.88 % w/w
o Yellow layer – Granules of pioglitazone 6.98 % w/w and Glimepiride granules 0.93 % w/w.
Batch compression was started on 51 Station compression machine (PR049) Initially all compression parameters were within the limit. After some time capping defect was observed, hence machine was stopped to find out the root cause.

Investigation:

  1. Investigation related to Method :

 Metformin hydrochloride SR Granules 59.88 % w/w manufacturing process involves sifting, dry mixing and wet granulation in FBE 1300 L, Drying in FBE 1300 L & lubrication in octagonal blender.
 Granules of pioglitazone 6.98 % w/w and Glimepiride granules 0.93 % w/w
manufacturing process involves sifting, dry mixing and wet granulation in RMG, Drying in FBE & lubrication in cage blender.
 Granulation parameters found well within limit ( Refer attached Granulation parameter Data).
 The compression activity was started on 20/Oct/2018 at 12:10 hrs. on 51 station compression machine (PR 049) in TM04 Area at the standard speed of 15 RPM ( Limit 15 to 25 RPM).
 During compression capping was observed at 12:20, hence the compression machine was stopped, batch was discontinued.
 On Date 20/Oct/2018 LOD was checked for both the granules. LOD of Metformin hydrochloride SR Granules 59.88 % w/w was observed as 4.68 % ( Limit: 3.5 to 4.5 % w/w) and LOD of pioglitazone 6.98 % w/w and Glimepiride granules 0.93 % w/w was observed as 2.13 % w/w ( Limit: 2.5 to 3.0 %).
 It was observed that LOD of metformin granules was observed as increased and LOD of pioglitazone 6.98 % w/w and Glimepiride granules 0.93 % w/w was decreased.
 Granulation parameters of incident batch and normal batch were checked and observed that LOD of metformin granules observed comparable and LOD of pioglitazone 6.98 % w/w and Glimepiride granules 0.93 % w/w observed more as compared to normal batch.
 On Date 04/Nov/2018 again compression was started on Korsch XL400 (PR040). Friability was failed and hardness observed as 10.20 to 12.00 kP ( Limit: 12 to 35 kp).
 As a part of Investigation LOD was checked on date 04/Nov/2018 and observed as 4.57 %w/w for Metformin hydrochloride SR Granules 59.88 % w/w and 2.83 %w/w for the granules of pioglitazone 6.98 % w/w and Glimepiride granules 0.93 % w/w.

  1. Investigation related to material.

 All the materials used in granulation were in approved state.
 Metformin hydrochloride SR Granules 59.88 % w/w from two batch Nos. were used in this batch ( B. No. A07461890 and A07461896).
 200gm sample of Metformin hydrochloride SR Granules 59.88 % w/w and 200gm sample of Granules of pioglitazone 6.98 % w/w and Glimepiride granules 0.93 % w/w was withdrawn for physical property test. Observations were as follows

Angle of Repose 	Hausner Ratio 

Batch No. IA18013 IA18013
Metformin hydrochloride SR Granules 59.88 w/w 35° 1.125
Flow Property Good Good
Granules of pioglitazone 6.98 % w/w and Glimepiride granules 0.93 % w/w 36° 1.111
Flow Property Fair Excellent

Based on results of Angle of Repose and Hausner ratio of lubricated granules, there was no issue to the flow of granules from hopper to die cavity.

  1. Investigation related to equipment and measurement.
     Details of compression machine used in compression were as follows:

Sr. No. Equipment name Equipment ID Qualification status

  1. 51 Station compression machine PR049 Qualified

  2. Korsch XL400 PR040 Qualified

    Preventive maintenance & breakdown of equipment 
    

 Preventive maintenance and qualification were carried out as defined schedule and no any abnormal observation was noted. No any breakdown observed during manufacturing and compression activity.

  1. Investigation related personnel.
     Involved technician and officers were trained and competent to perform the compression activity.

  2. Investigation related to Environment.
     Environmental condition Temperature & humidity maintained during manufacturing activity were as defined in BMR.

Root Cause:
 Probable root cause may be on storage LOD of Metformin hydrochloride SR Granules 59.88 % w/w found to be increased than initial and LOD for granules of pioglitazone 6.98 % w/w and Glimepiride granules 0.93 % w/w found to be decreased.

Corrective Action:

 Batch to be processed further on the approval of attachment to incident Investigation from production and batch to be continued further as per the procedure mentioned therein.
 Batch will be released only after complying finished product specification.

Risk Analysis:
 Batch was discontinued after observing capping defect, initial setting tablets were rejected. Batch will be continued as per approved procedure and if all parameters are complying as BMR per specification, hence no risk is anticipated.

Preventive Action:
 Protocol base study shall be performed for next five batches from granulation to compression stage and based on the evaluation further action plan shall be decided.


(YOGESH NARKHEDE) #14

Annexure - III
Investigation Report for I/PR/18/223
Purpose:
Purpose of this investigation is to identify the root cause and to determine appropriate corrective
and preventive actions for observed less yield in product Fornidd XR (Metformin hydrochloride
extended release 500 mg) tablet after completion of compression activity.
Scope:
o This is applicable to product Fornidd XR tablet,
o Product name: Fornidd XR.
o Generic name: Metformin hydrochloride extended release 500 mg tablets
o Batch No.A03971805
o Batch size: 515000.00 Tablets.
o Manufacturing date: Oct.2018
o Expiry date: Sep.2021
o Marketed by: I.E. Medica Inc., Philippines.
Background:
 During AQL checking of Fornidd XR (Metformin hydrochloride extended release 500 mg)
tablet, it has been found that some tablets having defect likewise minor black spots.
 Fornidd XR tablet is a single layer tablet, after compression it has been observed that tablet
having small black spots. To overcome this problem batch was inspected manually, after
inspection of tablet less yield found.
 Therefore, incidence report is initiated to address the root cause and to identify the preventive
action to prevent the recurrence of incidence.
Investigation:
 This report aims to identify root cause and propose actions for the black spot of product Fornidd
XR (Metformin hydrochloride extended release 500 mg) tablet under investigation and to
suggest suitable corrective and preventive action.
Investigation related to product: -
 Fornidd XR (Metformin hydrochloride extended release 500 mg) tablet is a single layer tablet,
for compression Giga Press machine 51 station was used.
 This investigation is carried to evaluate basic reason behind black spot of product Fornidd XR
(Metformin hydrochloride extended release 500 mg) tablet Batch No.A03971805.
 During compression of product Fornidd XR (Metformin hydrochloride extended release 500
mg) tablet Batch No.A03971805 black spot problem’s observed during compression activity.
 During routine checking by AQL it has been found that some tablets having defective tablets
likewise minute black spot.
 Entire batch was inspected for any visual defect before starting for blistering activity.
SOP Ref. No.: CQ/003 Page 2 of 4
Format No.: CQ/003/F-03
Investigation related to minor black particle: -
Details of magnesium stearate used in this formulation given below.
Product name Batch no. Magnesium stearate
vendor name
Magnesium stearate
batch no.
Fornidd XR (Metformin
hydrochloride extended
release 500 mg) tablet
A03971805 Valtris 0000066237
Details of magnesium stearate:-
o Material Name :Magnesium Stearate
o Material Code : 1500902
o AR No. : 10000251989
o RMS Reference No. : RMS0203
o Mfg. Date : 01.03.2018
o Expiry date : 01.03.2021
o Batch no. : 0000066237
o Vendor Batch no.: 010301899
o Quantity received : 793.800 KG.
o Issued in batch under investigation : 5.18 KG
o Manufacturer : VALTRIS SPECIALTY CHEMICALS
Evaluation:-
 Generation of black particle during processing of granulation were very less, main source of
minor black particle in this formulation may be magnesium stearate. Minor particles of
magnesium stearate when compressed on the surface of tablet look big or we can say due to
compression of particle on surface of clear white coloured tablet, it seems big. Particle clearly
visible when compressed on the surface of tablet. After compression if problem related to black
particle all tablets inspected for defected tablet & remove defective tablets.
Yield:
 After compression and after manually inspection both yields mentioned hear in table, we can
easily understand loss due to defected tables.
Batch No.
After compression After AQL & manually inspection
% Actual yield
Limit:
NLT 98%
% Theoretical
yield Limit:
NLT 95%
% Actual yield
Limit:
NLT 97%
% Theoretical
yield Limit:
NLT 94%
Fornidd XR
(Metformin
hydrochloride
extended release 500
mg) tablet Batch No.
A03971805
97.18% 99.55% 89.96% 92.89%
SOP Ref. No.: CQ/003 Page 3 of 4
Format No.: CQ/003/F-03
Evaluation: - In process parameters likewise weight variation, thickness, friability & hardness
were found within limit as per BMR. Yield of batch under investigation till inspection stage not
observed within the defined limit. Due to rejection by black particles yield of compressed tablet
was very less as compare standard batch size, it will cause a negative impact on final yield of tablet
after packing.
Investigation related to equipment:
 Equipment parameters setting was done as defined in respective batch record.
Sr.
No.
Equipment name Equipment ID Machine speed Observation
1 Giga press 51 station PR049 25 rpm OK
Preventive maintenance & breakdown of equipment
 Preventive maintenance and qualification was carried out as defined schedule and no any
abnormal observation was noted.
 Not any breakdown observed during manufacturing of Fornidd XR (Metformin hydrochloride
extended release 500 mg) tablet Batch No. A03971805.
Investigation related to personnel:
 Involved operator and manufacturing /IPQA officer during manufacturing/packing are trained
and competent to perform packing activity.
 Machine setting performed by concerned operator has been checked and confirmed that
chances of edge cut to the tablet might have generation because of improper setting of scraper
plate. This might be improper machine setting issue
Investigation related to environment:
 Environmental condition Temperature & humidity maintained during manufacturing activity
were as defined in BMR.
Root Cause:
 Most probable route cause for black particles is magnesium stearate which was used in this
formulation. Minor particles look big when compressed on the surface, due to compression on
surface it seems big. It’s very difficult to identify black particle during shifting, mixing
granulation & drying. Particle clearly visible when compressed on the surface of tablet. After
compression if problem related to black particle found we inspect it & remove defective tablets.
 If the compression machine setting is not proper, then chances of edge broking shall be
increased at the time if ejection of tablet. In this case setting of scraper plate & ejection of
tablet are reasons for breaking of edges.
Corrective Action:
 100 % visual inspection of tablet Fornidd XR (Metformin hydrochloride extended release
500 mg) Batch No. A03971805 done for detection of black spot.
 After inspection defected tablets discarded as per standard procedure. This may leads to
less yield at packing stage.
SOP Ref. No.: CQ/003 Page 4 of 4
Format No.: CQ/003/F-03
Risk Analysis:
 After evaluation of batch, it has been found that in process parameters of batch affected
were within predetermined specification limits of BMR.
 For detection of cuts, spots & visual defects, 100 % inspection of tablet of all above said
batch done.
 Friability, hardness, yield of manufacturing, yield of packing were within limit. After
evaluation of incident it has been cleared that this incident is in minor category and having
no impact on quality, safety & efficacy of drug.
 After inspection defected tablets discarded. Hence, we can say that there is no impact on
the quality of batch.
Preventive Action:
 Provide training to concerned operator about setting of compression machine so that such
type of incident not to repeat in future.
 Instruct to concerned person if similar black spot /particle observation noted in material
during granulation then same shall be highlight it senior and based on the observation same
shall be online rejected. Instruction given to production officers must we more alert in
future.
Prepared


(YOGESH NARKHEDE) #15

Annexure - III
Investigation Report Format I/PR/18/219
Purpose:
Purpose of this incident investigation is to identify the probable root cause for observed
two canister in bottle during packing activity of product Lansoprazole DR capsules USP
30 mg, (90’s count) batch number A2IOR006.
Scope:
This incident is applicable to,
Product: Lansoprazole DR capsules USP 30 mg, (90’s count)
Batch number: A2IOR006
Mfg. date: Sep.2018
Exp. date: Aug.2020
Batch size: 1575000 tablets
Pack size: Bottle pack of 90 capsules
Background:
Product Lansoprazole DR capsules USP 30 mg (90 count) batch number A2IOR006 is
manufactured for US Market (Client: Lifestar Pharma LLC).
Batch packing activity was initiated on countec bulk packing machine as per defined
number of capsule count (90 capsule) and one canister in bottle.
Bulk packing activity was initiated on countec bulk packing line. For packing of above said
product 150 cc HDPE bottle with 38 mm neck – DMF Grade ( SAP Grade : 2000997) and
CR cap 38 mm with induction seal – DMF Grade (SAP Code- 2001306) were used.
Capsules were filled as defined count in BPR i.e. 90 capsules per bottle and one 2 g
molecular sieve canister DMF grade (2001065) was inserted in bottle with help of canister
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.
Further these bottles labelled with outserter paste on bottle. Such 12 filled bottles and 2
bundle of medication guide packed in shipper.
During in process check by IPQA, two sachet were observed in bottle on line. This
observation was recorded in filled bottle before induction sealing.
Hence incident investigation report is initiated to find out the probable root cause and to
suggest suitable corrective and preventive action.
SOP Ref. No. : CQ/003 Page 2 of 6
Format No.: CQ/003/F-03
Investigation:
Investigation related to packing process:
Bulk packing activity of batch under investigation was initiated on countec bulk
packing line on 23/Oct/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,
canister 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 deionizing
and bottle mouth
= 4 mm
4 mm
Air Pressure 5 to 6
(kgf/cm2)
5.49
2
Multi-channel tablet &
capsule counting machine
No of counts per bottles : 90
90
Air pressure :05 to 0.6 Mpa
0.554
3 Canister inserter machine
One No. of 2 g molecular
sieve canister
01 No.
Air Pressure 5 to 6
(kgf/cm2)
5.38
4
Rotary capping machine
Torque: to be recorded
27.2 to 27.6 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 27.2 to 27.6 lb and induction sealing
parameter observed within defined range.
SOP Ref. No. : CQ/003 Page 3 of 6
Format No.: CQ/003/F-03
.
In process checks recording:
Sr.
No
Machine/
Process
Test Standard.
Parameter
Incident batch
(A2IOR006
1
Bottle
unscrambler
Machine
Speed
Record
Observation
20 to 47 Bottles /min
Distance
between deionising
nozzle &
bottle mouth
4mm OK
Visual
Inspection for
cleanliness
OK OK
2
Multichannel
counting
Machine
No. of units
filled
(Record the
observation)
Outlet A
10 – 13 bottles /min
Outlet B 08 – 14 bottles /min
Outlet 10 – 13 bottles /min
Outlet D 07 – 13 bottles /min
Conveyor
speed
For
information
6.8
3
Canister inserter
machine
01 count 01 count 01count
4
Rotary capping
machine/Capping
— Torque:
to be recorded
26.8 to 27.6 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
SOP Ref. No. : CQ/003 Page 4 of 6
Format No.: CQ/003/F-03
Evaluation: In process checks recorded during primary packing activity were found
complying with specification.
During IPQA in process check online on the conveyor one bottle with two canister was
observed. 04 more bottle were observed with two canister hence these bottles were
removed on line.
To rule out the possibility of packing of two canister in bottle of exiting packed shipper,
off line inspection packed bottle was done by weighing of filled and sealed bottle.
Physically weight of one canister (Can with molecular sieve) is around 3.7 to 3.9 gm.
Molecular sieve weight is around 1.9 to 2 gm. If bottle contains two canister, filled weight
of bottle will be increase by more than 3 gm. Average weight of filled & labeled bottle
with one canister and with outsert was observed, minimum 80.6 to 81.8 gm. Hence bottle
from packed shipper 1 to 258 were checked and only 06 bottles were observed with weight
more than 82-83 gm and these bottles were removed during off line inspection.
Initial investigation it was observed that it may be because of toppling of canister in
bottle intermittently in bottles leads to two canister insertion in bottle.
Further observation of two canister in bottle was taken with OEM to identify the
probable causes for filling of two canister in bottle:
Canister insertion get setting not done properly
Spring operation was not properly
Sensitivity of sensor
Canister insertion get setting was checked and found satisfactory and there were no
similar observation earlier. Hence it is ruled out.
Sensor functioning was checked and found satisfactory.
Spring operation it may jammed intermittently and may leads to insertion of two sachet
in bottle.
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 Issued
quantity
HDPE
Bottle150 cc
with 38 mm
neck - DMF
Grade
0000066277
0000066538
0000067509
10000252135
10000253656
10000259198
Shriji
polymer
17514
5062
10218
2310
CR Cap 33
mm with
induction seal

  • DMF Grade
    0000067256
    0000067257
    10000257644
    10000257652
    Shriji
    polymer
    17514
    16305
    1300
    SOP Ref. No. : CQ/003 Page 5 of 6
    Format No.: CQ/003/F-03
    Material
    name Batch number A.R. No.
    Vendor
    name
    Required
    quantity
    Issued
    quantity
    2 g molecular
    sieve canister
    DMF grade
    0000047049 90000009819
    Clarient
    corporation
    17514 18400
    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
    Canister insertion
    machine
    PR298 15-Nov-17 Nov-2022
    Preventive maintenance of equipment
    Sr.
    No.
    Equipment name Equipment ID
    Preventive
    maintenance done
    on
    Due on
    1
    Canister insertion
    machine
    PR298 Jul-18 Jan-19
    Root Cause:
    Exact root cause not identified however it may be probably because of both toppling of
    canister from hopper or jamming of spring for while dispensing of canister through
    canister inserter machine.
    Corrective Action:
  1. Off line inspection of packed 258 shipper bottle was done by individual weighing of
    bottle and only 06 bottles were observed and these bottles were removed.
  2. One person was kept for Online monitoring canister filling activity. Instructed
    concerned to monitor the canister insertion activity closely to avoid toppling of canister
    in bottle
    SOP Ref. No. : CQ/003 Page 6 of 6
    Format No.: CQ/003/F-03
    Risk Analysis:
    Observation was noted during online packing activity when bottles passing from canister
    inserter machine to rotary capping machine. This observation was noted before sealing of
    filled bottle hence immediately bottles present on conveyor belt removed online and
    verified for absence of two canister. Four bottles were observed and these bottles removed.
    01 to 258 shipper bottles were checked by weighing and observed bottles were removed
    and rejected. Shipper number 252, 02 bottles and in shipper number 254, 04 bottles were
    observed and these are removed. Further one dedicated person kept to verify the presence
    of only one canister in bottle. No similar observation noted later. Hence no risk identified
    to product quality.
    Preventive Action:
  3. To check the possibility of getting two canister because of jamming of spring of
    canister inserter machine, matter discussed with OEM telephonically and as per
    recommendations jamming of the spring might be due to the obstruction of bolt
    attached to the pusher plate shall be checked. Based on the observation preventive
    action shall be derived.
    Prepared

(YOGESH NARKHEDE) #16

Annexure - III
Investigation Report for I/PR/18/216
Purpose:
Purpose of this investigation is to identify the root cause and to determine appropriate corrective
and preventive actions for edge cut product Cetapin XR 1000(Metformin Hydrochloride Prolonged
Release Tablets IP 1000 mg) tablet after completion of packing activity.
Scope:
o This is applicable to product Cetapin XR 1000 tablet,
o Product Name : Cetapin XR 1000
o Generic Name : Metformin Hydrochloride Prolonged Release Tablets IP 1000 mg
o Batch No. : 0718020
o Batch Size : 515000 Tablets
o Manufacturing Date: Oct.2018
o Expiry date : March.2021
o Marketed by : Sanofi India Limited
o Manufactured by: Inventia healthcare Ltd.
Background:
 Cetapin XR 1000 (Metformin Hydrochloride Prolonged Release Tablets IP 1000 mg) is a
single layer tablet, for blistering of tablets Rotovac blister packing machine was used. During
routine checking by AQL, it has been found that some tablets having defect likewise minor
edge cut.
 Packing activity of above-mentioned product was planned on Rotovac packing line in PP-02
area on 20/Oct/2018. During packing edge cut on tablets were observed hence packing activity
stopped at 04:00 on 21/Oct/2018. Batch discontinued and removed from the area.
 Therefore, incidence report is initiated to address the root cause and to identify the preventive
action to prevent the recurrence of incidence.
Investigation:
 This report aims to identify root cause and propose actions for the observed edge cutting,
chipping, cracking & black spot of product Cetapin XR 1000 (Metformin Hydrochloride
Prolonged Release Tablets IP 1000 mg) tablet Batch No: 0718020 under investigation and to
suggest suitable corrective and preventive action.
Investigation related to product: -
 Cetapin XR 1000 (Metformin Hydrochloride Prolonged Release Tablets IP 1000 mg) is a
single layer tablet, for blistering of tablets Rotovac blister packing machine was used.
 This investigation is carried to evaluate basic reason behind edge cutting, chipping, cracking
& black spot of product Cetapin XR 1000 (Metformin Hydrochloride Prolonged Release
Tablets IP 1000 mg) tablet Batch No: 0718020.
 During compression of product Cetapin XR 1000 (Metformin Hydrochloride Prolonged
Release Tablets IP 1000 mg) tablet Batch No: 0718020 edge cutting, chipping, cracking &
black spot problem’s observed during compression activity.
SOP Ref. No.: CQ/003 Page 2 of 4
Format No.: CQ/003/F-03
 During routine checking by IPQA it has been found that some blister’s having defective tablets
likewise minute edge broken.
 Entire batch was inspected for any visual defect before starting for blistering activity.
Investigation related to minor black particle:-
Details of sodium CMC used in this formulation given below.
Product name Batch no. Sodium CMC
vendor name
Batch no. of sodium
CMC
Cetapin XR 1000
Metformin Hydrochloride
Prolonged Release Tablets
IP 1000 mg
0718020
Hyundae FECS
0000067094
Evaluation:-
 Generation of black particle during processing of granulation were very less, main source of
minor black particle in this formulation may be sodium CMC. Minor particles look big when
compressed on the surface, due to compression on surface it seems big. It’s very difficult to
identify black particle during shifting, mixing granulation & drying. Particle Cleary visible
when compressed on the surface of tablet. After compression if problem related to black
particle found we inspect it & remove defective tablets.
Hardness: -
 After evaluating BMR of product Cetapin XR 1000 (Metformin Hydrochloride Prolonged
Release Tablets IP 1000 mg) tablet Batch No: 0718020, hardness of both side found with in
limit. It’s easily understood by few readings which are given below in table.
Serial
no.
Observation
Hardness Limits: - 12.0 - 40.0 Kp Hardness Limits: - 12.0 - 40.0 Kp
For Left hand side For Right hand side
MAX. MIN. MAX. MIN.

  1. 29.40 Kp 19.90 Kp 22.60 Kp 14.00 Kp
  2. 26.00 Kp 15.70 Kp 23.50 Kp 15.70 Kp
  3. 20.30 Kp 18.20 Kp 23.50 Kp 15.40 Kp
  4. 18.80 Kp 17.70 Kp 19.80 Kp 18.20 Kp
  5. 21.20 Kp 19.20 Kp 20.10 Kp 16.90 Kp
    Friability: -
     Friability of both sides found with in standard limit give in BMR of product Cetapin XR
    1000 (Metformin Hydrochloride Prolonged Release Tablets IP 1000 mg) tablet Batch No:
  6. It’s maximum value found 0.489% for LHS & 0.425% for RHS. It’s easily
    understood by few readings which are given below in tabular form.
    SOP Ref. No.: CQ/003 Page 3 of 4
    Format No.: CQ/003/F-03
    Serial no.
    Friability Limit: - NMT 1.0 %
    w/w
    LHS RHS
  7. 0.322% 0.319%
  8. 0.489% 0.299%
  9. 0.436% 0.327%
  10. 0.386% 0.311%
  11. 0.218% 0.246%
  12. 0.182% 0.211%
  13. 0.241% 0.138%
  14. 0.153% 0.220%
  15. 0.263% 0.425%
    Max
    value
    0.489% 0.425%
    Yield:
     After compression and after inspection by ENCLONY both yields mentioned hear in table,
    we can easily understand loss due to defected tables.
    Sr.
    No.
    Batch
    No.
    after compression After AQL & Enclony inspection
    % Actual yield
    Limit:
    NLT 98%
    % Theoretical
    yield Limit:
    NLT 95%
    % Actual yield
    Limit:
    NLT 97%
    % Theoretical
    yield Limit:
    NLT 94%
  16. 0718020 98.28 98.62 97.84 96.06
    Evaluation: - Friability & hardness were within limit. Yield of batch under investigation till
    inspection stage observed within the defined limit.
    Investigation related to equipment:
     Equipment parameters setting was done as defined in respective batch record.
    Sr.
    No.
    Equipment name Equipment ID Machine speed Observation
    1 CIP- 29 station PR181 18 rpm OK
    Preventive maintenance of equipment
     Preventive maintenance and qualification was carried out as defined schedule and no any
    abnormal observation was noted.
    Investigation related to personnel:
     Involved operator and manufacturing /IPQA officer during manufacturing/packing are trained and
    competent to perform packing activity.
     Machine setting performed by concerned operator has been checked and confirmed that
    chances of edge cut or chipping to the tablet might have generation because of improper setting
    of scraper plate. This might be improper machine setting issue.
    SOP Ref. No.: CQ/003 Page 4 of 4
    Format No.: CQ/003/F-03
    Investigation related to environment:
     Environmental condition Temperature & humidity maintained during manufacturing activity
    were as defined in BMR.
    Root Cause:
     Most probable route cause for black particles is sodium CMC which was used in this
    formulation. Minor particles look big when compressed on the surface, due to compression on
    surface it seems big. It’s very difficult to identify black particle during shifting, mixing
    granulation & drying. Particle cleary visible when compressed on the surface of tablet. After
    compression if problem related to black particle found we inspect it & remove defective tablets.
     After investigation it has cleared that problem with product Cetapin XR 1000 (Metformin
    Hydrochloride Prolonged Release Tablets IP 1000 mg) is due to machine setting. Most
    probable route cause for chipping & cracking of tablet in improper machine setting.
     If the compression machine setting is not proper, then chances of edge broking shall be
    increased at the time if ejection of tablet. In this case setting of scraper plate & ejection of
    tablet are reasons for breaking of edges.
    Corrective Action:
     100 % inspection of edge cutting, chipping, cracking & black spot on tablet of complete
    batch done on enclony inspection machine.
     After inspection defected tablets discarded.
    Risk Analysis:
     After evaluation of batch, it has been found that in process parameters of batch affected
    were within predetermined specification limits of BMR.
     For detection of cracks, spots & visual defects, 100 % inspection of tablet of all above said
    batches done on enclony inspection machine.
     Friability, hardness, yield of manufacturing, yield of packing were within limit.
     After inspection defected tablets discarded. Hence, we can say that there is no impact on
    the quality of batch.
    Preventive Action:
     Provide training to concerned operator about setting of compression machine so that such
    type of incident not to repeat in future.
     Instruction given to production/IPQA officers must we more alert in future.

(YOGESH NARKHEDE) #17

Annexure - III
Attachment for Investigation Report for Incident I/PR/18/211

Purpose:
Purpose of this incident investigation is to identifying probable root cause and to suggest corrective and Preventive action for the observed more quantity posted in SAP for product Metformin Hydrochloride Extended Release Tablets USP 500mg B. No. 03118349.

Scope:
This incident investigation is applicable to product Metformin Hydrochloride Extended Release Tablets USP 500mg (4000926) B. No. 03118349.
B. Size: 925000 Tablets
Mfg. Date: Oct.2018
Exp. Date: Sep.2020

Background:
Metformin Hydrochloride Extended Release Tablets USP 500mg is one of product manufactured at Inventia. This product packed on Bottle Countec machine. The batch packing was initiated on 06/Nov/2018 and batch packing completed on 06/Nov/2018. After batch packing completion SAP quantity posting was done. But during quantity posting in SAP more 6000 Tablets posted.
This incident investigation report is initiated to find out the probable root cause and to suggest suitable corrective and preventive action.

Investigation:

The batch packing was completed on 06/Nov/2018 and total 151 shippers were packed. All in process and challenge test of machine were performed as per frequency given in Batch packing record. The sample quantity withdrawn by IPQA as per batch packing record and entries done by IPQA and packing persons. After batch completion reconciliation was done by production person and same was verified by IPQA. After reconciliation of packing materials, SAP entry was done.
As per packing total quantity transfer to finished goods store is 151 shippers (150 full and 151 no shipper loose with quantity 11 bottle) that is 905500 tablets and BSR note matches with SAP quantity. Total sample quantity record in batch packing record is the 1530 tablets as 1)retention Samples 500+500=100 tablets 2)Excise Sample 500 tablets 3) Sample for FP analysis (Initial, middle and end) 10+10+10=30 tablets. So as per packing, finished goods transfer quantity plus sample quantity including all samples means 905500+1530=907030 has to be post in SAP. But quantity posted in SAP was 913030 tablets instead of 907030 Tablets were more 6000 tablets posted.

 Investigation related involved person:

  1. All personnel involved in batch packing are trained in the respective activities of SAP
    entries.

Root Cause:

  1. Before quantity posting in SAP, calculation was done as per batch packing record. As per calculation done in batch packing record quantity post in COR6N and MIGO. Total 151 shippers was packed including loose shipper but during SAP posting total 152 shippers considered. Hence one shipper, tablets quantity that is 6000 tablets extra calculated and post in SAP.

  2. Root cause: Calculation error.

Corrective Action:

  1. Quantity 6000 Tablets to be rejected from SAP.
  2. Remaining correct quantity shall be release by QA.

Risk Analysis:

After batch packing, quantity calculation found 6000 tablets more posted in system it will impact on dispatch quantity. Quantity shall be corrected as per mentioned corrective action so there will be no risk of mismatch of quantity (actual packed and posted quantity).

Preventive Action:

  1. It is suggested to do calculation and quantity posted in SAP to be mentioned on reconciliation page.

Prepared By: Reviewed By: Approved By:


(YOGESH NARKHEDE) #18

Annexure - III
Attachment for Investigation Report for Incident I/PR/18/211

Purpose:
Purpose of this incident investigation is to identifying probable root cause and to suggest corrective and Preventive action for the observed more quantity posted in SAP for product K-Glim Trio 1mg B. No. ZRM1804.

Scope:
This incident investigation is applicable to product K-Glim Trio 1mg (4001230) B. No. ZRM1804.

B. Size: 455000 Tablets
Mfg. Date: Oct.2018
Exp. Date: Sep.2020

Background:
K-Glim Trio 1mg is one of product manufactured at Inventia site as commercial packing. This product packed on Elmac blister machine. The batch packing was initiated on 03/Nov/2018 and batch packing completed on 03/Nov/2018. After batch packing completion SAP quantity posting was done. But during quantity posting in SAP less 180 tablets posted by production officer Mr. Bhausaheb Mundhe.
This incident investigation report is initiated to find out the probable root cause and to suggest suitable corrective and preventive action.

Investigation:

The batch packing was completed on 03/Nov/2018 and total 141 shippers were packed. All in process and challenge test of machine were performed as per frequency given in Batch packing record. The sample quantity withdrawn by IPQA as per batch packing record and entries done by IPQA and packing persons. After batch completion reconciliation was done by production person and same was verified by IPQA. After reconciliation of packing materials, SAP entry was done.
As per packing, total quantity transfer to finished goods store is 141 shippers (140 full and 141 no shipper loose) that is 420600 tablets and BSR note matches with SAP quantity. Total sample quantity record in batch packing record is the 670 tablets as 1) Retention samples (Initial+Middle+End)160+140+140=440 tablets 2) Client samples 100+100=200 tablets 3) Sample for FP analysis (Initial, middle and end) 10+10+10=30 tablets. So as per packing, finished goods transfer quantity plus sample quantity including all samples means 420600+670=421270 tablets has to be post in SAP. But quantity posted in SAP was 421090 tablets instead of 421270 tablets were less 180 tablets posted.

 Investigation related involved person:

  1. All personnel involved in batch packing are trained in the respective activities of SAP
    entries.

Root Cause:

  1. Before quantity posting in SAP, calculation was done as per batch packing record. As per calculation done in batch packing record quantity post in COR6N and MIGO. But during calculation client sample consider less 180 tablets instead of 200 tablets. Client sample was 200 tablets means 100+100=200 tablets. But it calculates 100+100=20 tablets. Hence 180 tablets less post in SAP.

  2. Root cause: Calculation error.

Corrective Action:

  1. Quantity 180 Tablets to be added in SAP.
  2. After addition of remaining correct quantity batch shall be released as it is by QA.

Risk Analysis:

After batch packing, quantity calculation found 180 tablets less posted in system it will impact on dispatch quantity. Quantity shall be corrected as per mentioned corrective action so there will be no risk of mismatch of quantity (actual packed and posted quantity).

Preventive Action:

  1. It is suggested to do calculation of SAP posting quantity on reconciliation page and then quantity to be posted in SAP.

(YOGESH NARKHEDE) #19

Annexure - III
Investigation Report for I/PR/18/203
Purpose:
Purpose of this investigation is to identify the root cause and to determine appropriate corrective
and preventive actions for the increased % flap opening during drying activity of lot 4 to 6 for
product Isosorbide Mononitrate Tablet IP 20mg batch number A08661801.
Scope:
This is applicable to product Isosorbide mono nitrate granules, .
Product Name: Isosorbide Mononitrate Tablet IP 20mg
Batch No. : A08661801
Batch Size : 200.85Kg
Mfg. Date : Sep.2018
Exp. Date : Aug.2020
Market by : Bureau of Pharma PSUs of India- BPPI
Background:
Isosorbide Mononitrate Tablet IP 20mg is one of the products manufactured at Inventia site and
marketed for the Bureau of Pharma PSU of India-BPPI. Manufacturing process involves RM
sifting, wet granulation, wet granulation drying, sizing, lubrication. After lubrication these
granules are sent for compression.
During wet granulation drying for lot 04 to lot 06, percentage flap increased up to 42 to 45 against
BMR limit 35% flap opening, which is out of BMR specified limit.
Therefore, this incidence report is initiated to investigate, evaluate the impact & find out the root
cause for less yield at encapsulation stage.
Description of machine: -
Sr. No. Equipment name Equipment ID
1 FBE125L
PR036
Investigation:
 Drying process of Isosorbide Mononitrate granules completed in six lot, process started on
FBE125L at 22:38 on 27/SEP/2018 and completed on 11:21 at 28/SEP/2018. According to
standard predetermined parameters of granules drying, the standard limit of opening flap after
05 min is 40% & after 15 min is 35%.
 We can easily understand these parameters with the help of table easily.
SOP Ref. No.: CQ/003 Page 2 of 3
Format No.: CQ/003/F-03
 Involved operator and officer were properly trained & sufficient experience. Operator of
machine realised that bed is not fluidising properly, he opened the flap up to 42-45% in place
of 35% for proper fluidisation of granules.
 Chocking of figure bag pores partially is main problem in this incident. Batch size of above
said batch is more that’s why its divided in 6 lots.
 During different stages of drying shaking of Finger bags required at different time interval to
clear particles of material from pores of figure bag, for proper drying, improve CFM and avoid
partial chocking.
 To achieve required amount of air in CFM operator decided to open more % of flap to achieve
required high of fluidisation/CFM for proper drying. After above data evaluation it has been
cleared that this incident not having any impact on product quality.
Investigation related to equipment:
 Preventive maintenance and qualification were carried out as defined schedule and no any
abnormal observation was noted.
 Equipment parameters setting was done as defined in respective batch record.
Investigation related to personnel:
 Involved operator and manufacturing /IPQA officer during granulation are trained and
competent to perform manufacturing activity.
Batch
number
Lot
No.
Flap opening in
%
Actual
recording
CFM Drying time Loss on
drying
NMT
5%
A08661801
1st First 5 min. 50% 1015
66 min.
5- 15 min. 40% 595 1.58 %
15 onward 35% 245
2nd First 5 min. 50% 1064
45 min.
1.62%
5- 15 min. 40% 630
15 onward 35% 602
3rd First 5 min. 50% 1029 66 min. 2.71%
5- 15 min. 40% 574
15 onward 35% 217
4th First 5 min. 50% 987 42 min. 1.68%
5- 15 min. 40% 518
15 onward 45% 567
5th First 5 min. 50% 952 37 min. 0.68%
5- 15 min. 40% 511
15 onward 45% 483
6th First 5 min. 50% 987 39 min. 1.97%
5- 15 min. 40% 763
15 onward 42% 644
SOP Ref. No.: CQ/003 Page 3 of 3
Format No.: CQ/003/F-03
Investigation related to environment:
 Environmental condition Temperature & humidity maintained during packing activity were as
defined in BMR.
Root Cause:
Chocking of figure bag pores partially is main problem in this incident. Batch size of above said
batch is more that’s why its divided in 6 lots. During different stages of drying shaking of Finger
bags required at different time interval. To clear particles of material from pores of figure bag, for
proper drying, improve CFM and avoid partial chocking, shaking of figure bags required. If
responsible person is not shaking filter bag properly then this type of incidents takes place.
Corrective Action:
To achieve required amount of air in CFM operator decided to open more % of flap to achieve
required high of fluidisation/CFM for proper drying.
Risk Analysis:
Test results of granules like LOD found within limits as describe in BMR. In process checking
parameters of compression of said batch found within BMR limits. After analysing it has been
cleared that this incident not having any impact on product quality.
Preventive Action:

  1. Shake figure bag properly during shaking interval, if require than take more shaking time
    to remove the blockage from pores.
  2. Further 05 batches should be monitored for partial chocking of figure bags pore and
    required CFM. Based on the data required CFM limit for drying process to be defined.
    Prepared By: Reviewed By: Approved

(YOGESH NARKHEDE) #20

Annexure - III
Investigation Report for I/PR/18/202
Purpose:
Purpose of this investigation is to identify the probable root cause and to determine appropriate corrective and preventive actions for not achieving desired hardness (i.e. 13.0 Kp to 23.0 Kp) at standard speed 40 RPM to 70 RPM of compression machine (PR040).
Scope:
The Scope of this investigation is applicable to
Product Name: Metformin Hydrochloride Extended release Tablets USP 500 mg.
Batch No. : 03118317
Batch Size : 925000 tablets
Mfg date : Oct.2018
Exp date : Sep.2020
Machine and equipment ID: 29 station tablet compression machine (Korsch XL).
Equipment ID PR040.
Background:
Metformin Hydrochloride Extended Release Tablets USP 500 mg was manufactured at Inventia Healthcare limited for Market USA.
Manufacturing process involves milling, sifting, dry mixing, wet granulation, drying, sizing, lubrication, compression & inspection.
During initial setting of above said product on 29 station tablet compression machine (PR040) it was observed that the desired hardness (i.e. 13.0 Kp to 23.0 Kp) was not achieved at standard speed of compression machine 40 RPM to 70 RPM.
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.
SOP Ref. No. : CQ/003 Page 2 of 7
Format No.: CQ/003/F-03
Ishikawa (Fish bone diagram) for investigation:
Training Qualification
Machine setting Preventive /Breakdown
Maintenance
Lack of knowledge
Temperature /RH In-process testing equipments
In area
In process Test parameters
Flow property of granules In Process Controls
In process test Parameter
Particle size distribution Wet granulation in RMG 1200 L
Hardness Failure in Tablets
Man
Machine & Measurement
Material
Environment
Method
SOP Ref. No. : CQ/003 Page 3 of 7
Format No.: CQ/003/F-03
Investigation:

  1. Investigation related to Method:
    ➢ Manufacturing process involves milling, sifting, dry mixing, wet granulation, drying, sizing, lubrication, compression & inspection.
    ➢ All materials used in the manufacturing were analyzed and approved by QC prior to manufacturing.
    ➢ Line clearance was taken as per procedure mentioned in checklist and BMR.
    ➢ Required raw materials were dispensed as per bill of material.
    ➢ Granulation activity was performed as per stages mentioned in BMR. Method used was wet granulation in RMG 1200 L.
    ➢ Refer Attachment for granulation data:
    ➢ From the recorded granulation parameter of batch under investigation and earlier manufactured batches it was confirmed that all parameter observed in line with trend and within the specification.
    ➢ No failure/deviation observed during granulation & drying of this batch hence failure because of granulation/drying process can be ruled out.
    ➢ There were five batches in the campaign, the incident batch was the third batch where speed was reduced to 28 RPM. In previous two batches there was no observation of hardness failure with the speed of 40 RPM.
    ➢ As part of investigation, flow property of granules (angle of repose) was checked. Observed angle of repose of granule was 34 ℃ which show flow property of granules was good.
    ➢ During initial setting of above said product on 29 station tablet compression machine (PR040) it was observed that the desired hardness (i.e. 13.0 Kp to 23.0 Kp) was not achieved at standard speed of compression machine 40 RPM to 70 RPM. During initial setting at the speed of 40 RPM, hardness achieved was 8.70 to 10.60 Kp. Hence the speed was reduced to 35 RPM, at this speed, hardness was achieved between 8.70 to 10.60 Kp. Then speed was reduced to 28 RPM, hardness at this 28 RPM was observed between 13.90 to 15.00 Kp. With this speed all parameters were well within the limit. Compression Force Trend minimum and maximum force was as follows.
    B. No.
    Pre-compression force (kN)
    Main force (kN)
    Srel (%)
    03118317
    ( Incident batch)
    Min
    2.5
    60.6
    1.6
    Max
    4.3
    70.7
    3.6
    03118316
    Min
    2.2
    55.9
    1.7
    Max
    2.9
    63.5
    3.8
    From the above table it was clear that Pre-compression and main force was applied more as compared to previous batch wherein speed of the compression machine was 40 RPM.
    SOP Ref. No. : CQ/003 Page 4 of 7
    Format No.: CQ/003/F-03
  2. Investigation related to measurement:
    ➢ The equipments i.e. vibrosifter, RMG 1200 L, multimill, Co-mill, Fluidised bed Dryer (FBD 1300), octagonal blender 2000 L and 29 station tablet compression machine (Korsch XL) were in qualified status.
    ➢ Compression machine was started on 06/Oct/2018 at 04:00 hrs. One breakdown was observed during running of machine on 06/Oct/2018 at 09:30 hrs. Compression machine was producing abnormal sound, machine was stopped immediately.
    ➢ After rectification, machine trial was taken and then started the machine.
    ➢ Preventive maintenance status of the equipment used in granulation and compression were as follows.
    Sr. No.
    Equipment Name
    Equipment ID
    Preventive maintenance done on
    Preventive maintenance due on
    1
    Multimill
    PR012
    Jul/2018
    Oct/2018
    2
    Vibratory Sifter
    PR039
    May/2018
    Nov/2018
    3
    RMG 2000 L
    PR404
    Aug/2018
    Nov/2018
    4
    FBD 1300 L
    PR405
    May/2018
    Nov/2018
    5
    Co mill
    PR407
    Aug/2018
    Nov/2018
    6
    Octagonal Blender 2000 L
    PR309
    Sep/2018
    Mar/2019
    ➢ Hardness tester used for measurement of hardness was in calibrated status.
    ➢ Other instruments used for verification of compression parameter and granulation
    parameters are in calibrated status.
  3. Personnel:
    ➢ All operators & supervisors involved in manufacturing activity were trained & competent.
  4. Investigation related Environment:
    ➢ Temperature, humidity conditions in manufacturing areas were found to be well within specified limits of 19 to 27 ℃ and 40 to 65% RH.
  5. Investigation related to material:
    ➢ All the raw materials used in the batch were in approved state at the time of dispensing.
    ➢ Metformin API (Material code: 1000243) of Batch No.: 000066218; AR No. 10000251909) was used. Particle size of the API (Metformin HCL – Harman) used in the batch was observed as follows.
    SOP Ref. No. : CQ/003 Page 5 of 7
    Format No.: CQ/003/F-03
    Test
    Finished Product Batch No.
    API batch No. ( Supplier- Harman Finochem Limited)
    Specification
    Observation
    Particle Size (By Malvern master Sizer)
    03118317
    000066218
    D (0.1) NMT 20 micron
    D (0.1) 4 micron
    D (0.5) NMT 50 micron
    D (0.5) 31 micron
    D (0.9) NMT 100 micron
    D (0.9) 69 micron
    03118316
    0000066218
    D (0.1) NMT 20 micron
    D (0.1) 4 micron
    D (0.5) NMT 50 micron
    D (0.5) 31 micron
    D (0.9) NMT 100 micron
    D (0.9) 69 micron
    0000065455
    D (0.1) NMT 20 micron
    D (0.1) 7 micron
    D (0.5) NMT 50 micron
    D (0.5) 39 micron
    D (0.9) NMT 100 micron
    D (0.9) 81 micron
    03118309
    0000065455
    D (0.1) NMT 20 micron
    D (0.1) 7 micron
    D (0.5) NMT 50 micron
    D (0.5) 39 micron
    D (0.9) NMT 100 micron
    D (0.9) 81 micron
    03118302
    0000065948
    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
    03118306
    0000065454
    D (0.1) NMT 20 micron
    D (0.1) 17 micron
    D (0.5) NMT 50 micron
    D (0.5) 45 micron
    D (0.9) NMT 100 micron
    D (0.9) 84 micron
    03118300
    0000065948
    D (0.1) NMT 20 micron
    D (0.1) 5 micron
    D (0.5) NMT 50 micron
    D (0.5) 34 micron
    SOP Ref. No. : CQ/003 Page 6 of 7
    Format No.: CQ/003/F-03
    Test
    Finished Product Batch No.
    API batch No. ( Supplier- Harman Finochem Limited)
    Specification
    Observation
    D (0.9) NMT 100 micron
    D (0.9) 72 micron
    ➢ Same Batch No. API was used in batch No. 03118316 and in that no hardness issue was observed and batch was compressed on the same machine at the speed of 40 RPM.
    ➢ Angle of repose of lubricated granules was observed as 34 ℃. As per USP If the angle of repose is 31 to 35 ℃ then flow property of granules is good.
    ➢ Particle size distribution data of Validation batches after lubrication was as follows
    Test
    Batch No.
    A07451701
    A07451702
    A07451703
    Particles retained above # 14 mesh
    Nil
    Nil
    Nil
    Particles retained below # 200 mesh
    14.7
    29.6
    16.7
    Data for speed of compression machine observed as follows.
    Batch No.
    Speed of compression machine (RPM)
    Remark
    03118315
    40
    Normal speed of compression machine
    03118316
    40
    Normal speed of compression machine
    03118317
    28
    Reduced speed of compression machine
    03118318
    28
    Reduced speed of compression machine
    03118319
    28
    Reduced speed of compression machine
    Decrease in compression machine speed, result in increase in dwell time. There may be non uniform distribution of fines in granules, hence more compression force was required to achieve required hardness.
    Root Cause: Most probably may be due to non-uniform distribution of fines in lubricated granules, hardness observed on lower side.
    SOP Ref. No. : CQ/003 Page 7 of 7
    Format No.: CQ/003/F-03
    Corrective Action:
    ➢ Batch was compressed with reduction of machine speed to get the tablets hardness within limit. Batch to be released after complying finished product release specification.
    Risk Analysis:
    All compression parameter found complying with specification. With reduction speed, hardness of tablet was observed in the range 13.90 to 15 Kp and found complying. Appearance of tablet found complying with specification. Hence no risk to product quality
    Preventive Action:
    ➢ Bulk Density, Tapped Density, particle size distribution of granules and speed of compression machine to be monitored for next ten batches and based on the data action plan will be decided.
    Prepared By: Reviewed By: Approved By: