Investigation of incident


(YOGESH NARKHEDE) #42

Annexure III
Investigation Report Format I/PR/18/061
Purpose:
Purpose of this annexure is to capture the details of inspection of tablets due to black particle observed during packing stage for product Panfor SR 1000 mg, Batch number: PAF02350 with reference to incident number I/PR/18/061.
Scope:
The Scope of this annexure is applicable to -
Product name – Panfor SR 1000 mg
Batch No. – PAF02350
Batch Size –515000 Tablets.
Background:
Product Panfor SR 1000 mg Batch numbers PAF02350 were manufactured For market Client: Mega Lifesciences.
After compression AQL test performed. In AQL report it was observed that sample does not
confirm to the requirement of AQL established. Hence inspection activity done on Enclony machine (Area SP-14 Equipment ID No. PR439 ). In rejection summary it was observed that
maximum nos. of tablets reject as dirty tablets, stain tablets,edge dirty tablets, edge stain tablets and fat tablets. This report aims to identify root cause and to suggest suitable corrective and preventive action.
Investigation:
Details of yield:
Compression Yield
Range for yield 98%-102 % w/w
Actual 99.06 %
Quantity return for inspection
711.195 kg
516781 Nos.
Quantity transferred for packing after inspection 664.815 Kg
483043 Nos.
Qty.of tablets rejected during inspection
46.34 kg
33491 Nos.
Rejection Summary :
Dirty Tablets
3479 Nos.
Stain
16911 Nos.
Edge Dirty
4545Nos.
Edge Stain
3361 Nos.
Colour Dirty
1784 Nos.
SOP Ref. No.: CQ/003 Page 2 of 2
Format No.: CQ/003/F-03
Crack
2975 Nos.
Fat Tablets
390 Nos.
Tablet piece
01 Nos.
Challenge test
45 Nos.
Unsorted Defects
0 Nos.
Root Cause:

  1. Fat Tablets :
    Actual set thickness value is THK1 is 7.7 mm and of tablet found above this thickness value get
    rejected. During compression thickness limit is 7.50 to 7.83 mm. Some of the tablets thickness is observed more than mentioned THK1 limit in product recipe for enclony and defect is categorized as fat tablet.
    Actual specification is 7.30 to 7.90 mm and actual observation was in the range 7.49 to 7.83 mm. Parameter not set in recipe as per BMR limit for product.
    Compression was done on 23 station Sejong compression machine having AWC and it can get reject higher weight/lower weight and higher/lower thicknes tablets hence chance of generation tablet with higher thickness.
  2. Crack Tablets :
    Crack tablets rejection observed due to edge chipping tablets generated during compression.
    Observation is within the acceptance limit.
  3. Dirty Tablets/ Stain/ Edge Dirty/ Edge Stain/ Colour Dirty :
    It may be due to black particle present in Raw material for lubrication which was RM code

Corrective Action:
Set parameter in product recipe for enclony needs to be corrected in line with BMR specification.
Risk Analysis:
Since only good tablets transferred for next stage and bad tablets were sent for
destruction no product risk is anticipated.
Preventive Action:
Since the observation of black particle is originated from RM code 1500105, it is decided
to stop using this material instead of that same material from different code i.e 1500902 is
decided to use for next batches.
Other product recipe and set parameter need to be checked in line with defined limit with BMR.
Prepared By: Reviewed By: Approved By


(YOGESH NARKHEDE) #43

Annexure - III
Investigation Report Format I/PR/18/029
Purpose:
Purpose of this investigation is to identify the root cause and to determine appropriate
corrective and preventive actions for observed spillage of material below the RMG during
granulation activity of Oxcarbazepine Sustained Release Granules 66.67% w/w Batch
number: OOS18001IA.
Scope:
The Scope of this investigation is applicable to
Product name – Oxcarbazepine Sustained Release Granules 66.67% w/w.
Batch No. – OOS18001IA
Batch Size – 185.40 kg
Manufacturing date: Feb.2018
Expiry date: Jan.2020
Background:
The product Oxcarbazepine Sustained release granules 66.67 % w/w is manufactured at
Inventia Healthcare Pvt. Ltd for client Alkem laboratories Ltd.
Batch size of product is 185.40 kg. Granulation process involved sifting, binder solution dry
mix, Wet granulation, Semi drying, sifting and milling of semi dried granules, drying, sifting
and milling activity of dried granules and finally lubrication. This was first validation batch
as per Change management C/BD/17/037.
Granulation was initiated on 01/mar/2018 with proper line clearance in RMG 600L (PR004,
Room ID TM-02). Active and material code 1500008 were sifted together through 20 mesh
twice and then loaded in rapid mixer granulator and dry mixing was initiated for 10 minutes
at slow speed of impeller and chopper. After about 05 minute mixing was done (date
01/Mar/2018 from 03:41hrs to 03:46Hrs. and operator was Abhilesh Ingale), there was
observation of spillage of material below the RMG. About 17.58 kg material was observed
on floor.
Hence this incident investigation report is initiated to find out the probable root cause and to
suggest the suitable corrective and preventive action.
Investigation:

  1. Investigation related to material (input) :
    1.1 Input material i.e. API Oxcarbazepine and 1500008 were dispensed and sifted together
    as per process defined in BMR.
    Sr.
    No.
    Ingredient Material
    description
    Standard
    quantity
    (Kg)
    Stage of
    processing
    where these
    quantities
    added
    Weight after
    sifting
    1 1000129 Oxcarbazepine
    IP
    127.308 Dry mixing 140.520 kg
    SOP Ref. No. : CQ/003 Page 2 of 6
    Format No.: CQ/003/F-03
    Sr.
    No.
    Ingredient Material
    description
    Standard
    quantity
    (Kg)
    Stage of
    processing
    where these
    quantities
    added
    Weight after
    sifting
    2 1500008 Colloidal
    Anhydrous Silica
    IP/BP/Ph.Eur
    12.360 Dry mixing
    1.2 Material Oxcarbazepine IP and Colloidal Anhydrous Silica IP/BP/Ph.Eur were sifted
    together and were loaded in RMG for dry mixing activity.
    1.3 Total weight of loaded ingredient is 140.520 kg. Till the stage of incident only active and
    colloidal anhydrous silica were added. Added quantities were as defined in BMR. No
    deviation observed.
    1.4 On further verification and interrogation with concerned person confirmed that, after
    addition of material API and colloidal silicon dioxide, capacity of RMG was observed
    almost full and after addition of other excipient there may be possibility of overflow of
    material.
    1.5 Material COA of Oxcarbazepine (A.R.No. 10000219531) was checked and observed
    about 99.78 % particles are less than 50 microns and material description is off white to
    yellow crystalline powder and other material colloidal anhydrous silica
    (A.R.No.10000219489) is having bulk density before tapping was 0.046 g/ml and after
    tapping it was 0.052 g/ml. Actual observation was both materials are fine in nature and
    it occupies more volume of RMG and after addition of remaining excipient there may be
    possibility of overflow of material.
  2. Investigation related to Equipment :
    2.1 RMG minimum operating capacity is 77 kg and maximum operating capacity is 240 kg.
    2.2 By considering the maximum operating capacity of RMG 600, equipment was selected
    for granulation activity. Total batch size was 185.40 kg.
    2.3 However during actual granulation process, material Oxcarbazepine and Colloidal
    Anhydrous Silica were loaded and dry mixing was initiated for 10 minutes at slow speed
    of impeller and chopper. After about 05 minute mixing was done and there was
    observation of spillage of material below the RMG.
    2.4 RMG is provided with Teflon seal, Felt seal and Rubber Z seal. These seal are used to
    provide grip to RMG shaft during its movement.
    2.5 On further investigation, Teflon seal (Retainer) was observed worn out and subsequently
    resulted into heavy leakage of material.
    2.6 During 05 minutes dry mixing, about 17.58 kg granules were spilled below the RMG.
    These spilled granules are to be rejected and will be destroyed. There was about 12 %
    loss of granules observed from total dry mixed material.
    SOP Ref. No. : CQ/003 Page 3 of 6
    Format No.: CQ/003/F-03
    2.7 May be because of used material texture which is very fine nature. Probably because of
    observed leakage at teflon seal material loss was observed and which leads to impact on
    further yield of batch.
    2.8 Preventive maintenance of equipment was done on 27/Jan/2018 (Preventive maintenance
    checklist number 71863).
    2.9 Prior to granulation activity of product Oxcarbazepine Sustained Release Granules
    66.67% w/w, product to product changeover was done. RMG was thoroughly cleaned
    and as per checklist Impeller, chopper, vent bag assembly, lid gasket are to be dismantle
    during cleaning activity. After cleaning proper fitment of Impeller and chopper needs to
    be ensured. Trained persons are involved in cleaning activity and after cleaning proper
    fitment was to be ensured. Teflon gasket integrity issue may not identified at the time
    cleaning and RMG assembly by the concerned operator.
  3. Investigation related to Method (Granulation process) :
    3.1 Granulation process involves dry mixing of sifted active and colloidal silicon dioxide and other
    excipient in single lot. API and colloidal silicon dioxide both were loaded in RMG after sifting.
    No procedural deviation observed. Granulation activity was done as defined in BMR instructions.
    3.2 After fixing new teflon seal, remaining 05 minutes mixing was initiated. During remaining 05
    minute mixing, there was again observation of spillage of granules from RMG lid. Dry mixed
    quantity was reduced to 119.16 kg and again 3.78 kg loss was observed. Total 21.36 kg dry mix
    granules total loss was observed and same was destroyed.
    3.3 On further verification and interrogation with concerned person confirmed that, after
    addition of material API and colloidal silicon dioxide, capacity of RMG was observed
    almost full and after addition of other excipient there may be possibility of overflow of
    material.
    3.4 Material COA of Oxcarbazepine (A.R.No. 10000219531) was checked and observed
    about 99.78 % particles are less than 50 microns and material description is off white to
    yellow crystalline powder and other material colloidal anhydrous silica
    (A.R.No.10000219489) is having bulk density before tapping was 0.046 g/ml and after
    tapping it was 0.052 g/ml. Actual observation was both materials are fine in nature and
    it occupies more volume of RMG and after addition of remaining excipient there may be
    possibility of overflow of material.
    3.5 Hence further granulation activity was done in two lots.
    3.6 This dry mixed material were divided in two lots and other excipient proportionately
    added remaining 10 mixing was done in two lots. Further lubricants were added
    proportionately in the batch. Remaining excipient quantities were added as mentioned in
    below table;
    SOP Ref. No. : CQ/003 Page 4 of 6
    Format No.: CQ/003/F-03
    Sr.No. Ingredient Material
    description
    Standard
    quantity
    (Kg)
    Stage of
    processing
    where these
    quantities
    added
    Weight of excipient
    added based on the
    observed dry mixed
    granules
    1 – Dry mixed
    material
    Oxacarbazepine
    and Colloidal
    silicon dioxide
    140.520 kg Dry mixing 119.16 kg.
    Above quantity
    is divided into two lots
    Lot 1=59.58 kg
    Lot 2=59.58 kg
    1 1500086 Hypromellose
    USP (Methocel
    K100 LV)
    14.830 Dry mixing Lot -1=6.325 kg
    Lot-2= 6.325 kg
    2 1500139 Povidone
    IP/BP/Ph Eur (K

3.710 Dry mixing Lot -1= 1.582 kg
Lot-2= 1.582 kg
3 1500090 Lactose IP 7.679 Dry mixing Lot -1= 3.31 kg
Lot-2=3.31 kg
4 1500177 Crospovidone
BP/Ph
Eur(Polykovido
ne K10)
6.180 Dry mixing Lot -1=2.636 kg
Lot-2=2.636 kg
5 1500157 Maize Starch
IP/BP/PhEur
6.180 Dry mixing Lot -1=2.636 kg
Lot-2=2.636 kg
6 1500136 Polysorbate 80
(tween 80) IP
2.060 Binder
preparation
Lot -1=0.875 kg
Lot-2=0.875 kg
7 – Water for Binder
preparation
43.26 kg Wet
granulation
Lot -1 = 14.670kg
Wet
granulation
Lot-2= 14.670kg
8 Water for
rinsing
Wet
granulation
Lot -1=3.66 kg
SOP Ref. No. : CQ/003 Page 5 of 6
Format No.: CQ/003/F-03
Sr.No. Ingredient Material
description
Standard
quantity
(Kg)
Stage of
processing
where these
quantities
added
Weight of excipient
added based on the
observed dry mixed
granules
Wet
granulation
Lot -2=3.66 kg
9 1500145 Purified Talc
IP/BP/PhEur
2.060 Blending 1.74 kg
10 1500105 Magnesium
stearate
IP/BP/PhEur
2.060 Lubrication 1.74 kg
3.7 After above calculation remaining quantities of material used in dry mixing and blending
lubrication were destroyed.
4. Investigation related to personnel:
4.1 Involved person in granulation activity are trained and competent for granulation. There
was no manual intervention during dry mixing activity which leads to spillage.
5. Investigation related to environment:
5.1 Temperature, humidity conditions in manufacturing areas were found to be well within
specified limits of 19 to 27 °C and 40 to 65% RH.
Root Cause:
During investigation it was confirmed that observed material spillage which was because
of damaged teflon seal (retainer) and because of fine nature of Oxcarbazepine and
colloidal silicon dioxide and within 05 slow mixing out of 10-minute mixing material
was spilled and same was collected at the bottom of RMG.
This is equipment failure
Root cause Category: Equipment failure (Mechanical)
Corrective Action:

  1. Observed spilled material 17.58 kg granules is to be destroyed.
  2. Damaged teflon seal were replaced with new one.
  3. Remaining good granules (125.26 kg) were dry mixed for remaining 05 minutes and then
    composite sample and 10 point sample was withdrawn to detect the assay content and its
    uniformity throughout the dry mixed granules.
  4. Existing prepared binder is destroyed. Fresh binder solution for two lots prepared as per
    received good granules. Remaining extra quantities of excipient were destroyed.
  5. Finished product analysis results are complying with specification.
    SOP Ref. No. : CQ/003 Page 6 of 6
    Format No.: CQ/003/F-03
    Risk Analysis:
    Observed spillage of partially dry mixed granules quantity was about 12 % and it may
    have impact on the assay results and uniformity of
  1. Assay (same sample preparation calculated on different strengths)
    Strength
    As per Theorotical strength :
    88.50%w/w
    Actual strength (With process
    compensation): 91.15%w/w
    Assay 91.85%w/w , 103.8% of L.C 91.85%w/w , 100.8% of L.C
  2. Blend uniformity (same sample preparation calculated on different strengths)
    Location
    As per Theoretical strength :
    88.50%w/w
    Actual strength (With process
    compensation): 91.15%w/w
    T1 101.9 99.0
    T2 103.9 100.8
    T3 104.3 101.3
    M1 103.9 100.9
    M2 102.3 99.3
    M3 103.8 100.8
    M4 103.0 100.0
    B1 102.1 99.1
    B2 101.7 98.8
    B3 101.6 98.6
    Mean 102.9 99.9
    %RSD 1.0 1.0
    Results of assay and blend uniformity were observed within the specification and further
    excipient were compensated. No impact anticipated on product quality.
    Preventive Action:
  1. Granulation process will be done in two lots and BMR to be revised to include lot wise
    granulation activity.
  2. Preventive maintaince checklist will be revisited for addition of point for replacement of
    teflon retainer (teflon seal).Other RMG PM Checklist will be revisited for addition of
    point of teflon retainer replacement.
  3. At the time dismantling and assembly of chopper, impeller of RMG, Possibility of gasket
    integrity verification to be checked and if possible same shall be updated in cleaning
    checklist of RMG.
    Prepared By: Reviewed By: Approved By

(YOGESH NARKHEDE) #44

Annexure - III
Investigation Report Format I/PR/18/021
Purpose:
This investigation report prepared to evaluate probable causes for observed agglomerates to the pellets which results in less yield.

  1. Product Aceclofenac Sustained release pellets 60 % w/w
    Batch number: A02461802
    Observed Yield at SR coating stage: 91.19%, Range for % yield is 95 to 100 %
  2. Product Aceclofenac Sustained release pellets 60 % w/w
    Batch number: A02461804
    Observed Yield at Seal coating stage: 89.52%, Range for % yield is 95 to 100 %.
    Scope:
    This investigation report is applicable to following product and batches
  1. Aceclofenac Sustained release pellets 60 % w/w
    B. No. A02461802
    B. Size: 520 kg
    Mfg. Date: Jan.2018
    Exp. Date: Jun.2020
    Stage: SR coating stage
    In addition to above batch, one more batch of product Aceclofenac Sustained release pellets 60 % w/w where in observed agglomerates during seal coating activity hence same is also investigated and tracked in this incident
    Batch details as mentioned below;
  2. Aceclofenac Sustained release pellets 60 % w/w
    B. No. A02461804
    B. Size: 520 kg
    Mfg. Date: Feb.2018
    Exp. Date: Jul.2020
    Background:
    Aceclofenac SR Pellets 60% w/w is products manufactured at Ambernath facility for client :Pharose Remedies Ltd. Manufacturing process of this product involves drug layering in coating pan, followed by seal coating & SR coating in APCG 1200 & lubrication in octagonal blender 2000.
    For batch number A02461802, after completion of SR coating in 2nd number wurster cylinder, few agglomerates were observed. As per BMR procedure, pellets were sifted through 14 and 18 mesh. After sifting it was noticed that the agglomerate quantity is around 21.45kg & good pellets quantity is 473.7 kg ( % Yield: 91.19%, Range for % yield is 95 to 100 % ). The observation is abnormal and impacting on the final yield, therefore to document the failure & find out the root-cause this incident is raised.
    In addition to mentioned batch under investigation, agglomerates at seal coating stage was observed in batch number A02461804. During seal coating activity three times agglomerates generation was observed. First time observation, good pellets were observed 478.50 kg and about 1.5 kg agglomerates were observed. Second time observation, good pellets were observed 483.05 kg and
    SOP Ref. No. : CQ/003 Page 2 of 7
    Format No.: CQ/003/F-03
    about 2.5 kg agglomerates (loss) observed. Third time observation, good pellets were observed about 475.90 kg and about 22.05 kg agglomerates were observed.
    Hence this incident investigation initiated to find out the probable cause for getting agglomerates and less yield and to suggest suitable corrective and preventive action.
    Investigation:
    A. Product: Aceclofenac Sustained release pellets 60 % w/w Batch number: A02461802:
    Investigation with respect to Method, Machine, Man, Material and Environment was carried out.
    Investigation related Method:
  1. During SR coating activity, yield was observed less. i.e. 91.19 % (limit: 95 to 100 %).Less yield during SR coating activity observed which was because of observed agglomerates. These agglomerates observed may be because of improper spray gun pressure and spray pattern which was not monitored vigilantly.
  2. Factor affecting spray gun pressure and spray pattern are mentioned below;
    a. Atomization air pressure
    b. Peristaltic pump RPM
    c. Spray rate
    d. Silicon tube diameter ID/OD
    e. Chocking of spray gun during coating activity
    f. Improper fitting of spray gun
    g. Operational stoppage during coating activity
  3. Observed process parameters during coating activity are mentioned as follows;
    Stage
    Process Parameters /
    B. No.
    A02461802
    SR Coating (APCG 1200 )
    Inlet air Temperature(°C)
    To be adjusted to get specific bed temperature
    Set :32 to 41
    Act.: 34 to 48
    Bed Temperature(°C)
    Std.: 30 to 40
    Act.: 34 to 37
    Blower Speed
    Std.: 40 to 50
    Act .: 46
    Inlet air volume (CFM)
    Act.: initial 3017 and
    at the end of operation 2998
    P. Pump RPM
    10 RPM
    Spray Rate (g/Min)
    Std.: 450 to 550
    Act.:500
    Process Time
    Std.: 2hrs 15 min to 3 hrs. 15 min.
    Act. : 2 hrs. 02 min.
    Total suspension
    63.65 kg SR coating solution was sprayed.
    Drying
    Inlet air Temperature (°C)
    Set:25
    Actual:41 to 42
    Bed Temperature(°C)
    Std.:40 to 45
    Act.: 40 to 43
    SOP Ref. No. : CQ/003 Page 3 of 7
    Format No.: CQ/003/F-03
    Stage
    Process Parameters /
    B. No.
    A02461802
    Drying Time (min)
    20
    %Yield ( SR Coating & Lubrication)
    LOD (NMT 2.0 % w/w)
    0.19 % w/w
    Std. pellets wt.
    519.48 kg
    actual pellets wt.
    473.70 kg
    Rejection
    21.45 kg
    % Yield
    91.19 %
  4. All the process parameter are complying with predefined specification in BMR. APCG 1200 is having six gun for coating. After completion of SR coating activity, agglomerates were observed near to 2nd cylinder. Particular 2nd cylinder gun was checked and some sticked pellets were observed. May be during SR coating activity because of stuck pellets and SR coating solution droplet was generated, which further leads to agglomerates generation.
    This was observation noted for specific to 2nd cylinder gun after SR coating and no abnormality identified during operation with respect to spray rate and spray pattern. Another possibility specific 2nd cylinder gun may not fitted properly and which may further leads to droplet formation and further leads to agglomerates formation.
  5. Observed agglomerates were sifted about 21.45 kg agglomerates rejection was observed. This huge quantity of rejection leads to less yield. Prior SR coating initiation, these guns were cleaned and refitted.
  6. Other parameters such as atomization air pressure, Peristaltic pump RPM, Silicon tube diameter ID/OD are complying with BMR limit and no stoppage observed during SR coating activity.
    Investigation related to Machine/Equipment:
  7. All equipment involved in manufacturing are in qualified state and there was no breakdown observed with respect to any equipment.
  8. Equipment APCG 1200 used for SR coating activity.
  9. Process parameter setting was done as per BMR for SR coating activity in equipment, parameters details as mentioned below;
    Parameter
    Unit of measurement
    Standard
    Actual
    Distance from Cylinder from mesh
    mm
    50
    50
    Spray gun nozzle diameter
    mm
    2.0
    2.0
    Silicon tube diameter ID/OD
    mm
    8/12
    8/12
    Atomization air pressure
    Kg/cm2
    1.0 to 1.6
    1.0
    Needle operation air pressure
    Kg/cm2
    2.0
    2.0
    Load of seal coated pellets
    Kg
    513.96
    497.50
    Blower speed
    Hz
    40 to 50
    46
    Bed temperature
    °C
    30 to 40
    30 to 37
    Peristaltic pump RPM
    RPM
    10
    10
    Spray rate
    g/min
    450 to 550
    500
    SOP Ref. No. : CQ/003 Page 4 of 7
    Format No.: CQ/003/F-03
  10. All process parameters were set as per standard parameters mentioned in BMR.
  11. BBD alarm verification was done as per defined procedure and found satisfactory.
  12. Preventive maintenance of equipment was done on 19/Feb/2018, prior to this batch manufacturing.
    Investigation related to Man:
  13. All personnel involved batch manufacturing are trained in the respective activities.
    Investigation related Material:
  14. Issued material are from approved source and dispensed as per BMR. SR coating coating solutions were prepared as per BMR instruction.
    Investigation related Environment:
  15. Temperature and % RH maintained during manufacturing activity was within the defined acceptance criteria mentioned in BMR.
    Root cause:
    For batch number: A02461802 Less yield was observed because of observed agglomerate to the pellets. These agglomerates were generated because of chocking of spray gun no.2 which was because of sticking of pellets to the gun and droplet formation leads to generation of agglomerates however spray pattern was not vigilantly checked by concerned operator during operation. Or probably may be because of spray gun was not fitted properly which leads to generation droplet formation and leads to agglomerates formation. Further this was not identified by concerned operator. These agglomerates were sifted and then again seal coating activity was continued. This was happened might be because of less vigilance of concerned operator SR coating activity.
    In used machine APCG 1200 having six guns, out of six guns one gun chocking observed. After completion of SR coating activity, agglomerates were removed during sifting. May be because of gun chocking, from particular gun proper coating is not happened and which may resulted into higher side dissolution in batch.
    B. Product: Aceclofenac Sustained release pellets 60 % w/w Batch number: A02461804
    Investigation related to method:
  16. During investigation of above batch, another similar observation in another batch Number A02461804 was noted i.e. agglomerates formation during seal coating activity was noted. During seal coating activity three times agglomerates generation was observed. This batch seal coating was initiated on APCG1200. Seal coating activity was started on 21/Feb/2018 at 13:40 Hrs.
  17. First time agglomerate observed on 21/Feb/2018 at 14:45 Hrs. After sifting good pellets were observed 478.50 kg and about 1.5 kg agglomerates were observed. After sifting again seal coating activity was restarted on 21/Feb/2018 at 20:18 Hrs.
  18. Second time agglomerate observed on 21/Feb/2018 at 21:42 Hrs. After sifting good pellets were observed 483.05 kg and about 2.5 kg agglomerates (loss) observed. After sifting again seal coating activity was restarted on 22/Feb/2018 at 10:25 Hrs.
    SOP Ref. No. : CQ/003 Page 5 of 7
    Format No.: CQ/003/F-03
  19. Third time agglomerate observed on 22/Feb/2018 at 12:00 Hrs. After sifting good pellets were observed about 475.90 kg and about 22.05 kg agglomerates were observed. After sifting again seal coating activity was restarted on 23/Feb/2018 at 20:28 Hrs.
  20. Till time about 219.55 kg seal coat solution was sprayed and 83.90 kg seal coat solution from second lot was remained. Lot 3 seal coat solution about 151.65 kg quantity was remained.
  21. After rectification of observed breakdown again operation was restarted on 23/Feb/2018, again fourth time agglomerates were observed on 23/Feb/2018 at 22:08 Hrs. No separate breakdown was raised by production. There was again observation for cylinder alignment issue, this was verbally intimated to engineering and concerned engineering person has rectified the cylinder alignment and retighten the bolt of cylinder. After sifting good pellets were observed about 457.20 kg and about 20.30 kg agglomerates were observed. Because of insufficient steam pressure availability and all three APCG equipment not able to work at the same hence seal coating activity was stopped and again restarted on 27/Feb/2018 at 20:28 Hrs. and activity completed at 20:10 Hrs.
    Stage
    Process Parameters /
    B. No.
    A02461802
    Seal Coating (APCG 1200 )
    Inlet air Temperature
    To be adjusted to get specific bed temperature
    Set :32 to 41 °C
    Act.: 50 to 60°C
    Bed Temperature
    Std.: 35 to 45°C
    Act.: 35 to 44°C
    Blower Speed
    Std.: 40 to 50°C
    Act .: 46 to 50°C
    Inlet air volume (CFM)
    Act.: initial 2782and
    at the end of operation 2758
    P. Pump RPM
    16 to 20 RPM
    Spray Rate (g/Min)
    Std.: 750 to 1000
    Act.:768 to 960
    Process Time
    Std.: 7hrs 30 min to 8 hrs. 30 min.
    Act. : 8 hrs. 19 min.
    Total suspension sprayed
    455.00 kg
    Investigation related to Machine/Equipment:
  22. During seal coating there was observation of less fluidization of pellets hence breakdown for less CFM was raised and to verify the sifting of pellets, material was unloaded and at the same alignment of cylinder from mesh in upward direction found disturbed. Hence another breakdown raised for distance of cylinder.
  23. On further investigation it was confirmed that misalignment of cylinder was happened may be because of damage to thread of bolt. This misalignment of cylinder leads to improper spraying of seal coating solution and generation of agglomerates.
    SOP Ref. No. : CQ/003 Page 6 of 7
    Format No.: CQ/003/F-03
  24. Verification of alignment Preventive maintenance of equipment was done on 19/Feb/2018, prior to this batch manufacturing. Proper alignment of cylinder needs to be ensured by concerned production operator prior initiation of batch. If any such observation is noted then it should get rectified.
    Investigation related to Man:
  25. All personnel involved batch manufacturing are trained in the respective activities.
    Investigation related Material:
  26. Issued material are from approved source and dispensed as per BMR. Seal coating solutions were prepared as per BMR instruction.
  27. About 83.90 kg seal coat solution was crossed its holding period and hence additional required seal coating material was dispensed and further seal coating activity was continued.
    Investigation related Environment:
  28. Temperature and % RH maintained during manufacturing activity was within the defined acceptance criteria mentioned in BMR.
    Root cause:
    For batch number: A02461804, it was confirmed that misalignment of cylinder was happened may be because of damage to thread of bolt. This misalignment of cylinder leads to improper spraying of seal coating solution and generation of agglomerates.
    Corrective action:
    Corrective action against the observation for batch number A02461802:
  29. Reference incident number shall be mentioned in BMR.
  30. Good pellets were transferred to next stage.
  31. Instructed concerned to have more vigilance during coating activity.
  32. After getting higher dissolution results, addendum A1 to Deviation D/PR/18/007 was taken to evaluate further action plan.
    Corrective action against the observation for batch number A02461804:
  33. This is isolated incident, happened because of mechanical setting. This is one time setting hence as corrective action, Teflon packing and retreading to bolt was done and again refitting of all cylinder was done.
  34. Verification of alignment of cylinder needs to be ensured by concerned production operator prior initiation of batch. If any such observation is noted then it should get rectified.
  35. Till rectification of observed breakdown remaining solutions crossed their hold time period of 24 hours hence additional material was taken and solution will be prepared and further seal coating activity continued. Holding period seal coat solution was crossed hence solution was destroyed.
    SOP Ref. No. : CQ/003 Page 7 of 7
    Format No.: CQ/003/F-03
    Risk analysis:
    For Batch number: A02461802
    SR coated pellets with agglomerates were rejected and destroyed. These agglomerates were sifted through 12 and 14 mesh. Only good pellets were transferred to next stage. Because of sifting of agglomerates there may be possibility to have impact on dissolution results hence observed dissolution results of batch under investigation reviewed and results were observed on higher side. In used machine APCG 1200 having six guns, out of six guns one gun chocking observed. After completion of SR coating activity, observed agglomerates were removed during sifting. May be because of gun chocking, from particular gun proper coating is not happened and which may resulted into higher side dissolution in batch.
    Also because of removal of agglomerates leads to losses of pellets and which collectively leads to less yield.
    For Batch number: A02461804
    Pellets with agglomerates were rejected and destroyed. These agglomerates were sifted through 12 and 14 mesh. Only good pellets were transferred to next stage. Because of sifting of agglomerates there may be possibility to have impact on dissolution results hence dissolution results reviewed and found complying with specification. Hence no risk identified.
    Also because of removal of agglomerates leads to losses of pellets and which collectively leads to less yield.
    Preventive action:
  36. Retraining imparted to concerned person on pellets coating activity.
  37. Cylinder alignment is mechanical adjustment and same was observed because of damage to thread of bold and this is isolated incidence. However instructed concerned to verify the proper alignment of cylinder during machine setting.
    Prepared By: Reviewed by: Approved by

(YOGESH NARKHEDE) #45

Attachment III to incident I/PR/18/012
Purpose:
Purpose of this attachment III to incident number I/PR/18/012 is to identify the root cause
and suggest the corrective and preventive action for observed SAP entry error.
Scope:
The scope of this attachment III is applicable to
Product name: lansoprazole E/C pellets 8.5%w/w
Batch no: LAS03104
Mfg date: MAY.2018 & Exp date: APR. 2020
Investigation:

  1. Lansoprazole E/C pellets 8.5%w/w this batches were manufatcured for the Gmax
    pharmachem Co.Ltd
  2. Sample qunatity was to be withdrawn for rentention, excise and preshipment
    sample.
  3. Bulk packing activity of batch was completed on 26/May/2018 and as per
    procedure IPQA person was withdrawn sample 120 gm as retention,20 gm as
    excise and 100 gm preshipment sample was withdrawn by concerned IPQA
    person but missed to record the entry of pre shipment sample on BPR.Which he
    had done it later after reconcilition and SAP entry.
  4. Hence again packing reconciliation was corrected and again fresh SAP entry was
    taken.
  5. This was error happened because of negligence of concerned IPQA.
    Root cause:
    Negligence of concerned person during sample entry
    Personnel/Man error.
    Corrective Action:
    As corrective action, correct sample quantity (with additional 100 gm preshipment
    sample) SAP entry to be released by QC.
    Risk analysis:
    Transfer bulk quntity for dispatch and sample qunatity reconciliation is complying and no
    impact observed on dispatch quntity. Hence no risk identified.
    Preventive action:
  1. Instructions to be given to all concerned to have online sample quantity
    entries in BPR
    Prepared by : Reviewd by A

(YOGESH NARKHEDE) #46

Annexure - III
Investigation Report Format I/PR/18/002
Purpose:
Purpose of this investigation is to identify the root cause and to determine appropriate corrective and preventive actions for observed batch no A04531715 was run machine at 10 RPM & 16 RPM at initial setting.
During 16 RPM of initial setting of above said batch hardness were observed lower side. Machine setting was done to get rid of this observation with reduction in machine speed down to 15 RPM, Same observation of hardness at lower side was observed for batch no A04531716. Hence above said batches were compressed with speed of 15 RPM.
Scope:
The Scope of this investigation is applicable to
Product name – Metformin HCL ER tablets USP 500 mg
Batch No. – A04531715 & A04531716
Mfg. date: Dec.2017
Exp date: Nov.2020

Background:
Metformin HCL ER tablets USP 500 mg is single layer tablet and compressed by using granules of Metformin hydrochloride SR granules 59.88 % w/w for ROW market.
Stages involved in this products manufacturing process are dry mix, wet granulation, drying & lubrication. Product was compressed on 29 station compression machine (PR0181). Compression machine speed limit is mentioned as 20 to 25 RPM. Batch no A04531715 was run machine at 10 RPM & 16 RPM at initial setting. During 16 RPM of initial setting of above said batch, hardness was observed on lower side. Machine setting was done to get rid of this observation with reduction in machine speed down to 15 RPM. Similarly for batch number A04531716, machine speed was reduced i.e.15 RPM.
Hence this incident investigation report is initiated to find out the probable root cause and to suggest suitable corrective and preventive action.
Investigation:

  1. Compression parameter recorded during batch run verified and comparison is tabulated below;
    Batch No A04531716 A04531715
    Speed 15 RPM 10,16,15 RPM
    Compression machine 29 station 29 station
    Individual weight
    (793.25 to 876.75 mg) Min 0.82 0.817
    Max 0.85 0.855
    Hardness (10.00kp-25.0 Kp) Min 12.3 11.7
    Max 17.4 17.3
    Thickness (5.2kp to 5.8 Kp) Min 5.44 5.41
    Max 5.65 5.59
    Friability (NMT 1.0% w/w ) Min 0.11 0.154
    Max 0.28 0.428

Evaluation:
Based on the compression parameter were found satisfactory. However machine speed was reduced to get rid the hardness observation. Machine speed was kept lower than the specified limit in BMR.With reduced machine speed, tablet parameter i.e. hardness was found complying.
However this was extended to review of granulation parameter.

  1. Granulation parameter
    Sr.No. Granulation parameter A07061737 A07061738 A07061739 A04531601 A04531602 A04531603
    01 Description Almost white granules Almost white granules Almost white granules Almost white granules Almost white granules Almost white granules
    02 Bulk density 0.69 gm/ml 0.69 gm/ml 0.63 gm/ml 0.69 gm/ml 0.69 gm/ml 0.67 gm/ml
    03 Loss on drying (3.5 to 4.5 % w/w) 4.42 % 4.34 % 4.05% 4.17% 3.93% 4.34%
    04 % Particle sieve above 14# 1.06% 0.80 % 0.82 % Nil Nil Nil
    05 % particle weight of granules below 200 mesh 11.51 % 17.25 % 17.61% 16.0% 12.0% 13.8%
    06 Hausner ratio 1.103 1.069 1.156 1.31 1.23 1.21
    07 Compressibility index 9.375% 6.452% 13.513% 23.684% 18.919% 21.053%
    Remark Based on Hausner ratio and compressibility there were no issue with respect to compressibility Based on Hausner ratio and compressibility there were no issue with respect to compressibility Based on Hausner ratio and compressibility there were no issue with respect to compressibility Based on Hausner ratio and compressibility there were no issue with respect to compressibility Based on Hausner ratio and compressibility there were no issue with respect to compressibility Based on Hausner ratio and compressibility there were no issue with respect to compressibility
    Evaluation:
    Based on the physical parameter testing data, comparing with process validation batches granules properties were found satisfactory.
    For batch number A04531715, granules from Metformin Hydrochloride SR granules 59.88 % w/w Batch number A07061737 and A07061738 were issued and for batch number A04531716, granules from Metformin Hydrochloride SR granules 59.88 % w/w Batch number A07061738 and A07061739 were issued.
    Hausner’s ratio and compressibility index of used granules were observed good. No issue observed with respect to flow properties of granules. Probable cause of not getting hardness are as below
  2. lower loss on drying of granules, however loss on drying of granules was observed higher side to the defined specification hence possibility of loss on drying can be ruled out.
  3. Used punches and dies condition
  4. Insufficient compression load and person competency in machine setting.
    More fine granules present in granules.
  5. Machine setting:
    For batch number A04531715 Initial challenged test was performed as per BMR specification. After challenged test during intimal checks compression machine speed initially kept 10RPM was performed as per qualification protocol. After 10 RPM machine was run on 16 RPM because of hardness was found lower side of limit mentioned in BMR. Whole batch was manufactured on 16 RPM.
    For batch number A04531716 during Initial checks record for average weight and hardness, thickness and friability, hardness was not achieved hence batch was compressed on 15 RPM.
  6. Personnel :
    Operator involved Ravi and Pratik was already trained and competent.
  7. Reconciliation
    Reconciliation for A04531716 Handling waste was 5.700 kg where granules left over was 4.0kg and other rejection was 1.7 kg so % standard yield was 97.84% (Range for % yield 97-103%)
    Reconciliation for A04531715 Handling waste was 22.960 kg where granules left over was 3.970 kg and other rejection was 18.99 kg so % standard yield was 97.05% (Range for % yield 97-103%)
  8. How many batches manufactured on 29 and what was the speed and hardness.
    Till the date Aug.2018 Total 06 batches was manufactured all batches with product code (3001018) are manufactured on 53 sejong new compression machine. where all parameter of compression machine found within specification as well as compression machine speed was also within limit. No any abnormality were found during manufacturing activity. After this no batch was manufactured on 29 station compression machine.
    Root Cause:
    Improper Machine setting improper fine tuning in compression machine setting.
    This may be either because of fine variation in granulation. same Co-mill speed is under monitoring along with compression machine speed. Based on the same co-mill speed and machine speed to be evaluated.

Corrective Action:

  1. As all parameter and results found within specification hence batch was released.

Risk Analysis:
No risk to product quality as all physical parameter found within specification. After this batches total 04 batches of Metformin HCl ER Tablet USP 500 mg was manufactured and all batches was compressed on 53 sejong machine all parameters were within specification. Speed limit is also within limit.
Preventive Action:
Co-mill speed is under monitoring along with compression machine speed. Based on the same co-mill speed and machine speed to be evaluated


(YOGESH NARKHEDE) #47


(YOGESH NARKHEDE) #48


(YOGESH NARKHEDE) #49


(YOGESH NARKHEDE) #50


(YOGESH NARKHEDE) #51


(YOGESH NARKHEDE) #52

Annexure - III
Investigation Report Format
Attachment I to incident I/TT/18/007
Purpose:
Purpose of this attachment I to incidence number I/TT/18/007 is to identify the root cause
of observed incident of hardness challenges performed on low compression machine speed and to suggest the corrective and preventive action.
Scope :
The scope of this attachment is applicable to
Product Name: Metformin Hydrochloride 750 mg Prolonged Release Tablets.
Batch No. A1601801, A1601802, A1601803
Batch Size:180.55 kg
Mfg date : Mar.18
Exp date : Feb.20
Background :
Product Metformin Hydrochloride 750 mg prolonged release was manufactured at inventia healthcare for Europe market as exhibit batch.Same batch was planned for validation activity as per Protocol no. PVP/TAB/268.As per protocol sampling requirement was mentioned for Dry mixing stage, drying. Blending and lubrication, compression stage. As per the protocol challenges mentioned at the stage of compression low speed ,high speed,low hardness,high hardness to be performed. However low hardness, and high hardness to be perfom on optimum speed but the concerned IPQA performed at low speed (15RPM) instead of optimum speed (25RPM).Hence this investigation report is prepared to document probabale root cause and to suggest suitable corrective action and preventive action.
Investigation:

  1. This exhibit Batch were started for compression on dated 11/apr/2018 .As per the protocol the challenge test has to be perfomed at low speed ,high speed,low hardness,high hardness to be performed.
  2. The concerned IPQA person performed the low speed and high speed as per protocol details were recorded in protocol.
  3. However low hardness,high hardness challenge study was perfomed by concrened IPQA at low speed 15 RPM instead of optimum speed (25 RPM) and same sample was send for analysis.
  4. Concerned IPQA is already trained for the validation batches and exhibit batches.
    SOP Ref. No. : CQ/003 Page 2 of 4
    Format No.: CQ/003/F-03
  5. This error was happen due the concern IPQA not read the protocol vigilantly.
  6. QC Analysis performed and COA received on dated batch no A1601801 21/apr/2018 ,A1601802 on dated 23/apr/2018 and A1601803 on dated 26 /apr/2018 results were found satisfactory for the low hardness and high hardness .
  7. This error was happened because of concerned person had not read protocol properly and leads to error.
    Root Cause:
    Personnel/Man error- Protocol not read and not followed.
    Corrective Action :
    1.Retraining will be imparted to all concerned person to follow the protocol.
    2.Hardness challenge at optimum speed will be done on commercial batches .
    Risk Analysis:
    Standard parameters:
    Sr no.
    Parameters
    Acceptance criteria
    1
    Uniformity of weight (mg) 1150.00 mg ± 5% w/w (1092.5 mg to 1207.5 mg)
    2
    Hardness (Kp)
    20.0 Kp- 35.0 Kp
    3
    Thickness mm Target thickness: 7.2mm ± 0.3 mm (7.0 mm to 7.6 mm)
    4
    Friability (%)
    NMT 1.0% w/w
    Batch No. : A1601801
    Low hardness: (15 RPM)
    Sr no.
    Parameters
    Min Weight
    Max Weight
    Avg Weight
    LHS
    RHS
    LHS
    RHS
    LHS
    RHS
    1
    Uniformity of weight (mg)
    1.136
    1.133
    1.162
    1.158
    1.1527
    1.1479
    2
    Hardness (Kp)
    21.40
    22.00
    25.70
    25.40
    23.63
    23.97
    3
    Thickness mm
    7.37
    7.31
    7.41
    7.38
    7.38
    7.34
    4
    Friability (%)
    0.23%
    0.22%
    SOP Ref. No. : CQ/003 Page 3 of 4
    Format No.: CQ/003/F-03
    High hardness: (15 RPM)
    Sr no.
    Parameters
    Min Weight
    Max Weight
    Avg Weight
    LHS
    RHS
    LHS
    RHS
    LHS
    RHS
    1
    Uniformity of weight (mg)
    1.145
    1.138
    1.180
    1.158
    1.1563
    1.1494
    2
    Hardness Kp
    28.90
    26.40
    34.10
    32.20
    32.56
    29.53
    3
    Thickness mm
    7.23
    7.22
    7.30
    7.26
    7.24
    7.24
    4
    Friability (%)
    0.13%
    0.16%
    Batch No.: A1601802
    Low hardness: (15 RPM)
    Sr no.
    Parameters
    Min Weight
    Max Weight
    Avg Weight
    LHS
    RHS
    LHS
    RHS
    LHS
    RHS
    1
    Uniformity of weight (mg)
    1.139
    1.142
    1.199
    1.189
    1.1550
    1.1573
    2
    Hardness Kp
    21.80
    22.40
    30.10
    25.30
    23.85
    23.63
    3
    Thickness mm
    7.34
    7.38
    7.50
    7.43
    7.39
    7.41
    4
    Friability (%)
    0.13%
    0.15%
    High hardness: (15 RPM)
    Sr no.
    Parameters
    Min Weight
    Max Weight
    Avg Weight
    LHS
    RHS
    LHS
    RHS
    LHS
    RHS
    1
    Uniformity of weight (mg)
    1.138
    1.143
    1.192
    1.172
    1.1516
    1.1548
    2
    Hardness Kp
    27.30
    29.20
    33.40
    32.30
    30.07
    30.74
    3
    Thickness mm
    7.19
    7.24
    7.26
    7.28
    7.22
    7.26
    4
    Friability (%)
    0.08%
    0.10%
    Batch No. : A1601803
    Low hardness: (15 RPM)
    Sr no.
    Parameters
    Min Weight
    Max Weight
    Avg Weight
    LHS
    RHS
    LHS
    RHS
    LHS
    RHS
    1
    Uniformity of weight (mg)
    1.130
    1.139
    1.160
    1.158
    1.1463
    1.1467
    2
    Hardness Kp
    20.60
    20.60
    25.80
    25.20
    22.34
    22.85
    3
    Thickness mm
    7.34
    7.39
    7.40
    7.43
    7.37
    7.40
    4
    Friability (%)
    0.14%
    0.14%
    SOP Ref. No. : CQ/003 Page 4 of 4
    Format No.: CQ/003/F-03
    High hardness: (15 RPM)
    Sr no.
    Parameters
    Min Weight
    Max Weight
    Avg Weight
    LHS
    RHS
    LHS
    RHS
    LHS
    RHS
    1
    Uniformity of weight (mg)
    1.139
    1.137
    1.171
    1.162
    1.1551
    1.1507
    2
    Hardness Kp
    28.90
    28.40
    34.90
    34.40
    32.26
    32.17
    3
    Thickness mm
    7.24
    7.19
    7.30
    7.26
    7.26
    7.22
    4
    Friability (%)
    0.078%
    0.087%
    These challenges are required to evaluate the impact of high hardness and low hardness at optimum speed for compressed tablet.Analytical results were found complying with specification.Batch compression activity was done on optimum speed and all recorded compression parameter were found the within specification.
    Preventive Action :
  1. Instructions to be given to all concerned IPQA to read the protocol vigilantly and awareness Training to be imparted for the process validation Batches .
    Prepared By: Reviewed By: Approved By

(YOGESH NARKHEDE) #53

Risk Assessment No: RA/QA/016/18
Purpose:
To evaluate the risk associated with observed power failure due to burning of R phase lug over
potential transformer (P.T.) at MSEDCL substation dated 16/Oct/2018 from the period 04:50 hrs.
till 07:30 hrs. (Reference Incident No: I/EN/18/014).
Scope:
The assessment is prepared to evaluate the risk associated with activity which were in process
during the power failure, hence risk assessment is carried out to assess the impact on final
product quality.
Areas affected: All areas supported by AHU as below:

  1. Production process area
  2. Entire warehouse for Raw and packing material area
  3. Microbiology laboratory
    Followings are the Areas under Diesel Generator back up:
  4. Stability chambers & Walk in stability chambers
  5. Cold storage (2° to 8°C)
  6. QC instruments
  7. Micro instruments
  8. Capsule storage area
  9. IT Server
  10. Building Management System (BMS)
  11. Purified water system
  12. Controlled Sample Storage room
  13. All AHUs of Warehouse.
    IMPACTS OF POWER FAILURE:
  1. Equipment stoppage which may lead to incomplete operations and loss of productivity.
  2. Environmental parameter failure (Temperature, RH, differential pressure, Microbial load)
  3. Storage Condition which may lead to impact on product quality and material stability.
    List of manufacturing process ongoing during power failure:
    Room No: Product Name Batch Number Activity /Stage
    TM-01 Metformin HCl DC Granules 60% w/w MEF03420 Drying
    TM-02 Panfor SR 750 A07341811 Drying
    PM-03 CP for Lansoprazole DR capsule 15 & 30 mg 05318009 Seal coating
    PM-13 Domperidone SR pellets 30% w/w A02101809 Drug layering
    SP-13 Itopride HCl SR pellets 60% w/w A00541801 SR coating
    SP-11 Pregabalin SR Granules 46.15%w/w A06231811 Awaiting for Drying
    Page 2 of 8
    Others Activity areas during the time of power failure:
    Room No: Product Name Batch Number Activity /Stage
    TM-03 Metformin HCl SR Granules 60% w/w A07461896 Lubrication
    TM-04 Panfor SR 500 PAF01418 cleaning
    TM05 - - No Activity
    TM08 - - Cleaning
    TM-09 - - No Activity
    TM12 - - No Activity
    PM-01 Aceclofenac SR pellets 60 % w/w A08311813 Under breakdown
    PM-02 - - Under Qualification
    PM-04 - - Batch to Batch cleaning
    PM-07A Rablet I A04311803 Under breakdown
    PM-07B - - No activity
    PM-09 - - No activity
    PM-10 - - No activity
    PM-11 - - Batch to Batch cleaning
    PM-12 - - No activity
    SP-01 Panfor SR 500 PAF01418 Compression
    SP-02 Metformin HCl ER tablets USP 500 mg 03118329 Sizing
    SP-03 - - Batch to Batch cleaning
    SP-06 Duloxetine EC pellets 16.0 %w/w A04181815 Bulk packing
    SP-07 - - No activity
    SP-09 Levocetrizine DiHCl MD Tab 5 mg A04541805 Compression
    SP-10 - - No activity
    SP-12 Metformin HCl ER Tablets USP 500
    mg
    03118331 Sifting & Milling
    SP-14 - - No activity
    SP-15 K.Glim Trio 2 mg ZRN1807 Compression
    PP-01 Glimy M Forte (TP) A01621807 Packing
    PP02 - - No activity
    PP-03 Panfor SR 1000 PAF02379 Packing
    PP-04 Metformin HCl ER tab USP 500 mg 03118320 Packing
    PP-06 Panfor SR 500 PAF01416 Packing
    PP-07 - - Product changeover
    PP-08 - - No activity
    PP-09 - - No activity
    For the above mentioned activities, action was taken accordingly SOP QA/012. Impacted area
    operation were suspended. All sifted materials /compressed tablets were covered in the double
    Page 3 of 8
    polybag and were tied properly and kept in plastic container. After resume of power and restoring
    of environmental condition, further activity was initiated.
    Risk Evaluation and Action Plan:
  1. Activity : Drying
    Metformin HCl DC Granules 60% w/w, Batch No: MEF03420 was under drying process for
    lot 2 in FBE 1300 L installed in TM01.
    The drying process was started at 03:26 hrs. and the process was suspended due to power
    failure from period 04:50 hrs. till 07:30 hrs. .
    The material was kept on hold in FBE 1300 L in a closed condition. After power resume the
    process was restarted at 09:17 hrs; and completed at 09:32hrs.
    The final LOD was recorded as 3.94% w/w which was found within the acceptance criteria
    (NMT 3.5 - 4.5%w/w.).
    Considering the time for power failure and to evaluate the impact on drying process, 10 g
    sample of granules was withdrawn for the MLT. The results are reviewed and found within
    the acceptance criteria. Refer Annexure I.
    The finished product analysis result, COA are reviewed prior to release of batch and found
    within the limit. Hence no impact.
  2. Activity : Drying
    Panfor SR 750 Batch No: A07341811 was under drying process (Lot-3) in FBE 500L
    installed in TM01.
    The drying process was started at 03:55 hrs. and discontinued at 04:53 hrs. due to power
    failure.
    The material was kept on hold in FBE 500L in a closed condition. After power resume the
    process was restarted at 09:10 hrs. and completed at 09:34hrs.
    The final LOD was recorded as 2.95 % w/w which was found within the acceptance criteria
    (NMT 2.5- 3.5 %w/w.)
    10 gm sample was withdrawn for the MLT, test results for MLT, all the analytical results and
    finished product COA reviewed and found within the acceptance, no impact on product
    quality.
  3. Activity : Seal Coating
    Common pellets for Delayed Release Capsules for Lansoprazole 15 & 30 mg Batch no:
    05318009 was under progress for the seal coating stage in APCG1200 C installed at PM03.
    The coating activity was started on 02:10hrs, due to power failure the activity was suspended
    at the time of power failure.
    Immediately the pellets were unloaded and kept in to closed HDPE container.
    Page 4 of 8
    After the power resume, the weighed partially seal coated pellets was loaded at 12:00 hrs.
    and activity was started with the restore of all environmental conditions at 12:10 hrs. till
    15:27 hrs.
    The final LOD for seal coating was recorded as 0.86% w/w against acceptance of NMT
    1.2%w/w.
    Hence to confirm the impact 10 gm MLT sample was withdrawn, the results are reviewed
    and found satisfactory. Refer Annexure I
    Also considering the Hold time study for 24 hrs. of coating solution there was no impact on
    the product safety, efficacy, purity and quality.
    The Analytical in process test results, COA reviewed against specifications and found
    satisfactory. Hence no impact.
  4. Activity : Drug Layering
    Product Domperidone SR pellets 30 %w/w Batch no: A02101809 activity of drug layering
    was in process in Coating Pan 60”installed in PM13.
    The activity was in progress dated 15/Oct/2018 from 01:06 hrs, however the process was
    stopped due to agglomeration and sifting process was initiated.
    Due to the power failure from the period 04:50 till 07:30 hrs, the process for drug layering
    was not continued.
    The sifted pellets were kept in HDPE container tied in double poly bag.
    After power resume and restoring of environmental condition the process was initiated at
    09:15 hrs; final LOD was recorded as 0.40 % w/w which was within the acceptance
    criteria.i.e. NMT 2.0 %w/w hence no impact on the quality product.
    The total process time was recorded as 3hr.38 min which is within the standard parameters
    i.e2 hrs till 9 hrs.
    The drug pellets 10 mg sample was withdrawn for MLT test, the results are reviewed and
    found within acceptance Annexure I.
    Final LOD on the drug pellets drying was reviewed for Lot 1 (0.78% w/w) and Lot 2 (0.56 %
    w/w and found within acceptance limit i.e. NMT 2.0% w/w
    The final COA to be reviewed for the test results against the specifications before release.
  5. Activity: Drying
    Sustained release coating for Itopride HCl SR pellets 60% w/w Batch no: A00541801 was
    completed and was in continuous process for drying (Lot-1) in APCG 800 installed at SP-13.
    The drying activity was started at 04:45 hrs. and further the activity was suspended due to
    power failure at 04:51 hrs.
    The material was kept on hold in APCG 800 in a closed condition. After power resume the
    process was restarted at 15:16 hrs.,. and completed at 15:33hrs.
    The final LOD was recorded as 0.27 % w/w which was found within the acceptance criteria
    (NMT 1.5%w/w.).
    Page 5 of 8
    10 gm sample was withdrawn for the MLT, test results for MLT, all the analytical results and
    finished product COA reviewed and found within the acceptance, no impact on product
    quality.
  6. Drying:
    Pregabalin SR Granules 46.15%w/w Batch No: A06231811 was completed with wet
    granulation in RMG 150 L installed in SP-11 and was to be taken in continuous process for
    drying in FBE 125L(Lot-1).
    Due to power failure the activity for drying was not initiated and the material was kept in
    RMG 150L in closed container.
    After power resume the drying process was started at 09:26 hrs. and completed at 10:26
    hrs.
    The final LOD was recorded as 2.55 % w/w which was found within the acceptance criteria
    (NMT 2.0 - 3.5 %w/w.) No any abnormal observation were recorded during compression.
    10 gm sample was withdrawn for the MLT, test results for MLT, all the analytical results
    and finished product COA reviewed and found within the acceptance prior release ,no
    impact on product quality.
  7. Impact on Products stored in production area :
    The environmental conditions in BMS system were recorded and reviewed for WIP
    areas(AHU 3622 & AHU3650) and day store area (AHU 3632). There was no excursions
    observed for AHU 3650 and AHU 3632, for AHU 3622 and AHU 3604 (Cater in WIP 04,
    05, 06, 07) there is excursion recorded for minimum 2.30 hrs., refer Annexure II. But it does
    not allow any impact on the product considering time period of power failure and in process
    material, granules and compressed tablets hold time study.
    Based on Annexure II, the MKT calculated for AHU 3622 i.e. 26.4°C and AHU 3604 i.e.
    27.2 °C.As per storage conditions mentioned in USP monograph, “Controlled room
    temperature” indicates a temperature maintain thermostatically that encompass the usual and
    customer working environment of 20 to 25°C that result in a MKT Calculated to be NMT
    25°C and allows excursion between 15 to 30 °C.
    All the materials are stored in closed container, also as a preventive action during power
    failure, man and material movement in storage area restricted to avoid the dust accumulation
    where the risk of contamination can be minimized.
  8. Microload in production areas:
    The Microload was evaluated by the settle plate exposure method in the pellet manufacturing,
    scale up,primary packing corridors and tablet manufacturing areas at operations the results
    for the TAMC (total Aerobic Microbial Count cfu/plate) was found within the acceptance
    i.e NMT 150 cfu/plate.Refer attached as Annexure III.
    Page 6 of 8
  9. Impact on Products in Warehouse:
    Warehouse:
  10. Temperature and Relative humidity recorded by the software xiltrix reviewed and found
    satisfactory.
  11. The co-relation of mentioned AHU/AC unit with xiltrix substation is indicated as below :
    Sr.no AHU No. Substation
    with
    channel
    Catering area Minimum
    temperature
    Maximum
    temperature
    Mean kinetic
    temperature
    1 AHU3666 TI-001-4 RM/PM
    Storage area
    19.9°C 22.0°C 20.9°C
    2 AHU3667 TI-002-2 BSR 19.8.°C 21.8°C 20.9°C
    TI-002-3
    20.2°C 22.8°C 21.4°C
    3 AHU3668 TI-001-3 RM/PM
    Storage area
    19.7°C 21.7°C 20.6°C
    4 AHU 3669 TI-001-1 RM/PM
    Storage area
    19.9°C 22.6°C 21.2°C
    TI-001-2 20.5°C 23.3 °C 21.8°C
    5 AC UNIT TI-005-3
    TI-005-4
    EHGC
    Storage area
    21.6°C
    48.2 %RH
    22.6°C
    54.7 % RH
    22.0°C
    NA
    TI-006-1
    TI-006-2
    22.6°C
    46.7 %RH
    23.2°C
    52.3 %RH
    22.9 °C
    NA
    TI-006-3
    TI-006-4
    23.0°C
    45.6 %RH
    23.6°C
    50.5 %RH
    23.3°C
    NA
  12. AHU 3617 TI-004-2
    TI-004-3
    RM
    Dispensing
    staging area
    21.0°C
    18.8°C
    23.2°C
    20.8°C
    21.6°C
    19.3°C
    • TI-003-3 Cold Storage
      I
      1.6°C 6.4°C 4.7°C
    • TI-003-4 Cold Storage
      II
      5.2°C 6.5°C 5.9°C
      Page 7 of 8
  13. As per storage conditions mentioned in USP monograph, “Controlled room temperature”
    indicates a temperature maintain thermostatically that encompass the usual and customary
    working environment of 20 to 25°C that result in a MKT Calculated to be NMT 25°C and
    allows excursion between 15 to 30 °C.
  14. All storage areas AHUs catered under DG Backup and the recorded temperature during this
    period captured in Xiltrix system is reviewed, refer Annexure III.From the above based data,
    the MKT recorded for all AHUs are well within the acceptance.
  15. AHU 3637 storage area for EHG capsules the temperature is within the limit and Relative
    humidity was at lower limit for about 30 min refer attached Annexure III, However as per
    environmental SOP QA/020 the excursion of ±5% Relative humidity for 3 hrs. is acceptable.
    Hence no impact.
  16. As well as no any RM Dispensing and sampling activity was in progress power failure.
  17. Dispensed Secondary packing;
    Material stored such as shipper, cartons, label no storage condition claimed by manufacturer.
    Hence no any impact.
  18. Impact in Microbiology Section:
    No any impact in Microbiology department as no any activity was in process and all
    instruments are cater under DG supply.
  19. Safety Impact:
    Before initiating any activity like switching ON power supply, AHU’s etc. as per SOP,
    safety clearance was taken from Engineering department.
  20. Action taken on after resume of power:
    After resume of power, it was ensured that all environmental condition were achieved in
    the area as per SOP QA/012 and thereafter further manufacturing activity was initiated.
    Abbreviations:
    PP Primary Packing
    TM Tablet Manufacturing
    SP Scale-up
    DG Diesel Generator
    RM Raw Material
    RS Relative Substance
    RMG Rapid Mixing Granulator
    FBE Fluid Bed Equipment
    ER Extend Release
    SR Sustain Release
    Page 8 of 8
    USP United State Pharmacopoeia
    LOD Loss On drying
    BMS Building Management System
    AHU Air Handling Unit
    SOP Standard Operating procedure
    QA Quality Assurance
    MSEDCL Maharashtra State Electricity Distribution Company Limited
    HT breaker High tension breaker
    APCG Anish particulate Coater Granulator
    Conclusion:
    Based on the above data the risk impact on the product quality nullifies, also based on stability
    data, hold time study, MLT test results for respective in process product risk is ruled out.
    The failure doesn’t have any major impact on product/material quality.As per batch release
    practice, all material and product testing results are reviewed prior to release. No impact to
    product quality anticipated.
    Attachments:
    ANNEXURE I: MLT Test Results.
    ANNEXURE II: BMS RECORD /Mean kinetic temperature.
    ANNEXURE III: XILTRIX /AHU 3637 BMS Record/ Results for Environmental monitoring by
    settle plate.
    Prepared By Checked By Approved By

(YOGESH NARKHEDE) #54

Risk Assessment No: RA/QA/005/18
Purpose:
To evaluate the risk associated with observed power failure due to power tripped from HT breaker
in Ambernath plant on dated 28/Jul/2018 from the period 07:50 hrs. till 22:10 hrs.(Reference
Incident No: I/EN/18/012).
Scope:
The assessment is prepared to evaluate the risk associated with activity which were in process
during the power failure, hence risk assessment is carried out to assess the impact on final
product quality.
Areas affected: All areas supported by AHU as below:

  1. Production process area
  2. Entire warehouse for Raw and packing material area
  3. Microbiology laboratory
    Followings are the Areas under Diesel Generator back up:
  4. Stability chambers & Walk in stability chambers
  5. Cold storage (2° to 8°C)
  6. QC instruments
  7. Micro incubators
  8. Capsule storage area
  9. IT Server
  10. Building Management System (BMS)
  11. Purified water system
  12. Controlled Sample Storage room
  13. All AHUs of Warehouse.
    IMPACTS OF POWER FAILURE:
  1. Equipment stoppage which may lead to incomplete operations and loss of productivity.
  2. Environmental parameter failure (Temperature, RH, differential pressure, Microbial load)
  3. Storage Condition which may lead to impact on product quality and material stability.
    List of manufacturing process ongoing during power failure:
    Room No: Product Name Batch Number Activity /Stage
    TM02 Telmisartan Granules 16.67%w/w 0718003 Drying
    PM09 Aceclofenac SR pellet 60%w/w A07261802 Drug layering
    PM04 Common pellets for Duloxetine Delayed
    Release Cap USP 20,30 & 60 mg
    03318011 Barrier Coating
    SP02 Metformin HCl SR 59.88% w/w 03118287 Granulation
    SP06 Fluoxetine tab USP 60 mg 12218006 Solution preparation
    Others Activity areas during the time of power failure:
    Page 2 of 7
    Room No: Product Name Batch Number Activity /Stage
    TM01 - - No Activity
    TM-03 Obimet SR 1gm A08571806 Lubrication charging
    activity
    TM-04 - - No Activity
    TM05 - - No Activity
    TM08 Metformin HCl ER tab USP 500 mg 03118221 Challenger test
    TM-09 - - No Activity
    TM12 Metformin HCl ER tab USP 500 mg 03118225 Compression
    PM-01 - - No Activity
    PM-02 - - Under Maintenance
    PM-03 - - Cleaning
    PM-07A - - No Activity
    PM-07B Lansoprazole DR cap 30 mg 05518004 Encapsulation
    PM-10 - - Under Qualification
    PM-11 - - No activity
    SP-01 - - cleaning
    SP-03 Aceclofenac SR pellets 60%w/w A00551804 Drug blending
    SP-07 - - No activity
    SP-09 Panfor SR 1000 PAF02362 Compression
    SP-10 - - Cleaning
    SP-11 - - Cleaning
    SP-12 Proglutrol 500 PRL01103 RM Sifting
    SP-13 - - Under Maintenance
    SP-14 Metformin HCl ER tab UPS 500 mg 03118220 Tablet Inspection
    SP-15 Glyciphage G1 Forte IA18028 Packing
    PP-01 Obimet SR (TP) A08561805 Packing
    PP02 - - No activity
    PP-03 Dianorm M OD A00641807 Packing
    PP-04 - - No activity
    PP-06 - - No activity
    PP-07 Glyciphage G1 IA18028 Packing
    PP-08 - - No activity
    PP-09 Aceclofenac SR pellets A02461813 Labelling
    For the above mentioned activities, action was taken accordingly SOP QA/012. Impacted area
    operation were suspended. All sifted materials /compressed tablets were covered in the double
    polybag and were tied properly and kept in plastic container. After resume of power and restoring of
    environmental condition, further activity was initiated.
    Page 3 of 7
    Risk Evaluation and Action Plan:
  1. Activity : Granulation
    Telmisartan Granules 16.67% w/w Batch No: 0718003 was under drug granulation process
    in FBE 500 L installed in TM02.
    The drying process was started at 04:43 hrs.
    The material was kept on hold in FBE 500L in a closed condition. Immediately after power
    failure, the remaining solution was kept in closed container and stored properly till the
    resume of power. At the same time, LOD was checked and recorded as 2.34 %w/w.
    After power resume the process was restarted at 23:51 hrs,. and completed at 04:54 hrs. .The
    final LOD was recorded as 1.14% w/w which was found within the acceptance criteria (NMT
    1.5%w/w.).
    Considering the time for power failure and to evaluate the impact on granulation process, 10
    g sample of granules and drug solution was withdrawn for the MLT.
    Also considering the hold time study for 24 hrs. of drug binder solution. No impact on the
    product safety, efficacy, purity and quality anticipated.
    The results are reviewed and found within the acceptance criteria. Refer Annexure I.
    The finished product analysis result will be reviewed prior release of batch.
  2. Activity : Drug Layering
    Product Aceclofenac SR pellets 60 %w/w batch no: A07261802 activity of drug layering was
    in process for Lot no: 02 in Coating Pan 48”installed in PM09 area.
    The activity was in progress dated 28/Jul/2018 from 06:00 hrs. However it was stopped
    immediately due to the power failure from the period 07:50 till 22:10 hrs.
    As per procedure the material was unloaded at 08:11 hrs. After power resume and restoring
    of environmental condition the process was initiated at 02:45 hrs; final LOD was recorded as
    0.40 % w/w which was within the acceptance criteria.i.e. NMT 2.0 %w/w hence no impact
    on the quality product.
    The total process time was recorded as 4hr.10 min which was within the standard parameters
    i.e 3hrs.45 min till 4hr.30 min
    The drug pellets 10 mg sample was withdrawn for MLT test, the results are reviewed and
    found within acceptance Annexure I.
    The final COA to be reviewed for the test results against the specifications before release.
  3. Activity : Barrier Coating
    Common pellets for Delayed release capsules for Duloxetine batch no: 03318011 was under
    progress for the Barrier coating stage in APCG1200 C installed at PM04 area.
    The coating activity was started on 27/Jul/2018 at 14:55 hrs. , due to power failure the
    activity was suspended at the time of power failure .
    Immediately the pellets were unloaded and kept in to closed HDPE container.
    After the power resume, the material was loaded at 00:28 hrs. and activity was started with
    the restore of all environmental conditions at 13:04 hrs. till 02:29 hrs.
    Page 4 of 7
    The final LOD for barrier coating was recorded as 0.43% w/w against acceptance of NMT
    1.5 %w/w.
    The total standard process time was not impacted.i.e 16hrs -19 hrs. as the recorded total
    process time was 18 hrs. 01 min.
    Hence to confirm the impact 10 gm MLT sample was withdrawn, the results are reviewed
    and found satisfactory. Refer Annexure I
    Also considering the Hold time study for 24 hrs of coating solution there was no impact on
    the product safety, efficacy, purity and quality.
    The Final test results to be reviewed against specifications before the release of batch.
  4. Activity: Granulation
    Metformin HCl SR granules 59.88%w/w was in progress for drying process in SP02 area for
    Lot -2 of batch A07261802.
    The drying process was started on 28/Jul/2018 at 05:12 hrs. In the FBD 1300L, due to power
    failure the process was stopped. The granules were in FBD 1300 l in closed system further
    the activity was initiated at 23:17 hrs. After the resume of power, the activity was completed
    at 23:50 hrs.
    The final LOD was achieved 3.07%w/w for Lot-2 against the limit i.e 2.5 -3.2%w/w.
    Microbial limit test was performed for product Metformin Hcl SR granules, the results found
    within acceptance. Refer Annexure I
    The batch is under reduced testing, based on LOD test the results are found satisfactory.
    Hence no impact on quality product.
    The Final test results to be reviewed against specifications before the release of batch.
  5. Activity: Coating
    Fluoxetine tablet Coating Solution preparation was ongoing in the area SP06 area for batch
    no:12218006
    The activity was started on 28/Jul/2018 at 5:50 hrs till 06:53 hrs, the activity for film coating
    was to be continued however due to power failure the process was not started.
    The solution about 9.520 kg was kept on hold in closed container, Also the solution was
    sampled for the MLT test and upon completion of film coating activity the tablets were also
    sampled for the MLT test.
    The hold period established for the coating solutions is about 24 hrs.
    Considering The MLT results, hold time study, no impact on product quality.
  6. Impact on Products stored in production area :
    The environmental conditions in BMS system were recorded and reviewed for WIP
    areas(AHU 3622 & AHU3650) and day store area (AHU 3632) There is excursions
    observed, refer Annexure II but it does not allow any impact on the product considering the
    hold time study, also As per storage conditions mentioned in USP monograph, “Controlled
    room temperature” indicates a temperature maintain thermostatically that encompass the
    usual and customar working environment of 20 to 25°C that result in a MKT Calculated to be
    NMT 25°C and allows excursion between 15 to 30 °C.
    Page 5 of 7
    Based on the values the MKT calculated for all areas are not NMT 25°C, hence no impact.
    All the materials are stored in closed container, also as a preventive action during power
    failure, man and material movement in storage area restricted to avoid the dust accumulation
    where the risk of contamination can be minimized.
    All API, in process material, granules and compressed tablets have the Hold time study.
  7. Impact on Products in Warehouse:
    Warehouse:
  8. List of finished products and raw/packing material were stored in stores area attached as
    Attachment III.
  9. Temperature and relative humidity alarm recorded by the software xiltrix reviewed and found
    satisfactory.
  10. The co-relation of mentioned AHU/AC unit with xiltrix substation is indicated as below :
    Sr.no AHU No. Substation
    with
    channel
    Catering
    area
    Minimum
    temperature
    Maximum
    temperature
    Mean kinetic
    temperature
    1 AHU3666 TI-001-4 RM/PM
    Storage
    area
    22.3°C 26.7°C 24.5°C
    2 AHU3667 TI-002-2 BSR 21.6°C 26.6°C 24.3°C
    TI-002-3 21.8°C 27.1°C 24.6°C
    3 AHU3668 TI-001-3 RM/PM
    Storage
    area
    22.2°C 26.5°C 24.4°C
    4 AHU 3669 TI-001-1 RM/PM
    Storage
    area
    22.9°C 27.5°C 25.1°C
    TI-001-2 23.4°C 28.2 °C 25.7°C
    5 AC UNIT TI-005-3
    TI-005-4
    EHGC
    Storage
    area
    20.8°C
    40.2 %RH
    22.5°C
    52.1 % RH
    21.8°C
    NA
    TI-006-1
    TI-006-2
    18.9°C
    45.8 %RH
    21.5°C
    57.9 %RH
    20.5 °C
    NA
    19.9°C
    43.2 %RH
    22.4°C
    57.9%RH
    48.5°C
    TI-006-3 NA
    TI-006-4
  11. As per storage conditions mentioned in USP monograph, “Controlled room temperature”
    indicates a temperature maintain thermostatically that encompass the usual and customary
    Page 6 of 7
    working environment of 20 to 25°C that result in a MKT Calculated to be NMT 25°C and
    allows excursion between 15 to 30 °C.
  12. From the above based data, the MKT recorded for all AHUs are not well within the
    acceptance. However long term stability 25oC / 60% RH, 30 oC / 65% RH and accelerated
    stability 40oC / 75% RH study available for all the approved APIs.
  13. The AHU 3637 for (RQ 36) Relative humidity was found out of limit on higher side with
    maximum of i.e. 60.52% (limit 45 ±5 %) for the dated 28/Jul/2018.However at present only
    Empty capsules are stored in that area for which required RH limit is 40 – 65 %. Hence no
    impact on the material.
  14. Cold room storage I &II temperature conditions temperature was observed with excursion for
    less than a hour during the period of power failure refer Annexure III, however SOP for the
    environmental monitoring allows the excursion of ± 2◦c temperature for 1hr ,Hence no
    impact.
    All storage areas AHUs catered under DG Backup and the recorded temperature during this
    period captured in Xiltrix system is reviewed, refer Annexure III. As well as no any RM
    Dispensing and sampling activity was in progress after power failure. No excursion was
    reported.
  15. Dispensed Secondary packing (AHU 3601):
    Material stored such as shipper, cartons, label however no storage condition claimed by the
    manufacturer. Hence observed temperature excursion doesn’t have any impact.
  16. Empty drum storage, sampling and dispensing staging area. (AHU 3617):
    The Xitrix report attached as Annexure III, No material was stored in the staging hence there
    is no impact. Also as per storage conditions mentioned in USP monograph the MKT value
    calculated is recorded as 22.9°C, which is NMT 25°C hence no impact evaluated.
    Impact in Microbiology Section:
  1. The BMS data for AHU 3649 (Micro LAF room) reviewed the humidity conditions were
    found out of limit for approx 15 hrs., in this area water analysis and MLT transfer for
    pathogen test(test for specified microorganism)100 cfu suspension preparation was in
    process after power failure. Above mentioned activities were discontinued, upon power
    resume the further activity was completed, however no impact was observed as all the test
    reports were found well within the acceptance criteria. Also the negative and positive
    control reports are within limits, the environmental conditions for Laminar Air flow
    records reviewed and found satisfactory refer Annexure IV
    AHU 3630(Micro Autoclave room) in microbiology section was reviewed refer Annexure
    II and found that the RH reading for AHU 3630 was found out of limit however which
    does not have any impact ,as no analysis activity was in process an Autoclave room. As
    dehydrated media in the autoclave was stored the media was examined visually for any
    impact, no any abnormal observation were recorded. Refer Annexure IV.
    Page 7 of 7
    Safety Impact:
    Before initiating any activity like switching ON power supply, AHU’s etc. as per SOP,
    safety clearance was taken from Engineering department.
    · Action taken on after resume of power:
    After resume of power, it was ensured that all environmental condition were achieved in
    the area as per SOP QA/012 and thereafter further manufacturing activity was initiated.
    Abbreviations:
    PP Primary Packing
    TM Tablet Manufacturing
    SP Scale-up
    DG Diesel Generator
    RM Raw Material
    RS Relative Substance
    RMG Rapid Mixing Granulator
    FBE Fluid Bed Equipment
    ER Extend Release
    SR Sustain Release
    USP United State Pharmacopoeia
    LOD Loss On drying
    BMS Building Management System
    AHU Air Handling Unit
    SOP Standard Operating procedure
    QA Quality Assurance
    MSEDCL Maharashtra State Electricity Distribution Company Limited
    HT breaker High tension breaker
    Conclusion: Based on the above data the risk impact on the product quality nullifies, also based
    on stability data, hold time study, MLT test results for respective raw material, in
    process/finished product.
    The failure doesn’t have any major impact on product/material quality. As per batch release
    practice, all material and product testing results will be verified prior to release. No impact to
    product quality anticipated. The root cause for the HT breaker tripped is investigated under the
    incident I/EN/18/012 accordingly the CAPA will be tracked.
    Attachments:
    ANNEXURE I: MLT Test Results.
    ANNEXURE II: BMS RECORD
    ANNEXURE III: XILTRIX RECORD
    ANNEXURE IV: Microbiology
    Prepared By Checked By Approved By

(YOGESH NARKHEDE) #55

Annexure III to incident I/PR/18/044
Purpose:
Purpose of this annexure is to investigate the cause of less yield after compression of Panfor SR 500 B.no PAF01419 on 23 station sejong tablet compression machine .
Scope:
The Scope of this annexure is applicable to
Panfor SR 500 B.no.PAF01419
Planned B.Size:1030000Tablets.
Mfg. Date-Oct .2018
Exp. Date Sep.2021
Marketed by: Mega life sciences
Background
Panfor SR 500 B.No. PAF01419 single layer product, with composition Metformin HCL SR granules 59.88%. Compression of Panfor SR 500 B.no.PAF01419 compression done on 23 station sejong machine. In this batch less yield observed at compression stage i.e. 97.64 % limit is 98.00 % to 103.00%.
Investigation:

  1. Panfor SR 500 B.no.PAF01419 is single layer product, with composition of Metformin HCL SR granules 59.88.It is first batch of campaign (second batch was PAF01420).Compression done on 23 station sejong machine.
  2. Before start compression initial setting done on 13.10.2018 and run machine from 00:35 on 14.10.2018 and stop on 05:45 on 14.10.2018 due to weekly off.
  3. Again compression started at 10:05 on 15.10.2018 and stopped at 23:00 on 15.10.2018 , before that second time initial setting done.
  4. Again third time initial setting done On 16.10.2018 because machine stopped due to punch tightness observed on 04:25 on 16.10.2018 .
  5. In this batch less yield at compression stage i.e. 97.64 % limit is 98.00 % to 103.00% observed it may be due to three times initial setting done and rejection generated during initial setting .
  6. Yield reconciliation are as follows :
    1.)Planned theoretical batch size : 860.05 kg ≈ 1030000 tablets
    2 )
    Calculated theoretical yield (Kg) :881.50 kg ≈1055688
    3 )
    Actual Quantity transferred for next stage: (Kg) 857.81 kg ≈1028919Nos
    4 )
    Sample Quantity (a+b+c)
    Kg
    No
    SOP Ref. No.: CQ/003 Page 2 of 2
    Format No.: CQ/003/F-03
    a) In process Sample
    2.865
    3436
    b) QC Sample
    0.092
    110 Tablets
    c) Other sample during compression

Total (a+b+c)
2.957
3546
5.0 ) Handling Waste (d+e) = 20.43 kg
d) Metformin HCL SR granules left over in Kg: 1.31kg
e) Reject (i+ii+iii) : 19.12 kg
Qty of Tablet rejected
Kg
No
i. During compression
*13.410 +**4.100
21002
ii. During Inspection

iii. Other rejection
***1.610

6.0 )Total Rejects = Step 5 + a = 23.295 kg
7.0)% Standard Yield {( Step 3+Step 4) / Step 2 X100 } = 97.64 %
Range for % yield = 98-103 %
8.0 )% Reconciliation {(Step 3 + Step 4 + Step 5) / Step 2 X 100} = 100.08 %
*Initial setting rejection :13.410 kg, **In process rejection 4.10 kg, &
***Dust rejection= 1.610 kg
Root Cause:
Probable root cause for less yield due to more rejected tablets generate during 3 times initial setting.
Corrective Action:
Tablets compressed during initial setting was rejected and sent for destruction .
Risk Analysis:
There is no impact on the quality of product is anticipated. All compression parameter found complying with specification.
Preventive Action:
Due to stoppages initial setting done 3 times hence preventive action can to be suggested .
Prepared By: Reviewed By: Approved By


(YOGESH NARKHEDE) #56

Annexure - III
Investigation Report Format I/PR/18/041

  1. Purpose:
    Purpose of this investigation report is to identify the probable root cause for the observed leak test failure during packing activity of product CZ –COLD Batch number A04911801.
  2. Scope:
    This incident investigation is applicable to observed leak test failure on strip pack machine for product CZ –COLD Batch number A04911801.
  3. Background:
    CZ -COLD capsules is one of the product manufactured at Ambernath site. The product is encapsulated on AF 90T machine & packed on strip packing machine.
    During strip packing, while carrying out AQL by IPQA, leak test of one strip was found fail. Also pocket cut was observed. The incidence was reported during AQL of shipper number 80. Hence strip packing activity was stopped and leak test of previous packed shipper no 37 to 109 were checked.
    Leak test of shipper nos 37 to 42 were found OK & shipper no 43 to 109 were found failed. Hence shipper number 43 to 109 were given for defoiling and partial good quantity from shipper number 01 to 42 were dispatched.
    Meantime investigation was extended to machine setting, used change part and its condition and used printed packing material for packing activity, operator training competencies.
  4. Investigation:
     Primary packing material was issued for packing activity as defined in BPR.
     Printed aluminum foil 292 mm (0.03 mm) SAP code 2005716 from SAP batch number 0000055952 and 0000061430 and plain aluminum foil SAP batch number 0000061672 was issued for the batch packing.
     Machine setting was done with the use of above mentioned packing material. Initial NFD challenges and leak test was found OK. Involved strip pack machine is qualified and preventive maintenance was done as per defined frequency.
     As per instructions given in BPR, leak test was checked at the start of batch, printed aluminum foil roll change and plain aluminum foil roll change. Leak test up to shipper number 42 were found OK.
     Packing activity initiated on 09/Mar/2018 and it was continued on next days.
     Observed leak test failure strips were checked and confirmed that there was observation of slight pocket cut to the strips and leak test failure observation was noted in the knurling of strip.
    SOP Ref. No. : CQ/003 Page 2 of 3
    Format No.: CQ/003/F-03
     On further investigation it was confirmed that observed leak test failure may be due to over tightness of aluminum foil or may be because of extra sealing pressure might have applied at the time change in aluminum foil roll. This over tightness or more sealing pressure leads to leak test failure.
     Involved operator is trained and competent however proper foil tightness was not ensured by concerned operator or may be extra sealing pressure applied i.e. machine setting issue which resulted into leak test failure. Sealing pressure adjustment is mechanical setting and once it is set then it should not be changed without manual intervention.
     At the time of change in foil roll, concerned operator might have over tensed the foil roll or may applied more sealing pressure which leads to pocket cut observation and leak test failure observation.
     Batch packing activity was initiated on strip pack machine with the use of change part layout number SE-1076.
     Other process parameter such as sealing temperature and sealing roller condition was found satisfactory.
  5. Root Cause:
    Upon investigation leak test failure may be due to improper tightness of aluminium foil roll or may be more sealing pressure applied during sealing activity. This foil tightness or sealing pressure might have got disturbed at the time of change in foil roll. Further proper setting was not ensured by concerned operator.
  6. Corrective Action:
     Identified leak test failure strips were defoiled. Defoiled capsules were inspected and then taken for packing.
     Leak test verification frequency increased to half an hour.
     Machine setting was ensured by loosening the tightness of foil and by ensuring sufficient sealing pressure and ensure no extra sealing pressure.
  7. Risk Analysis:
     Identified leak test failed shippers were segregated, defoiled and after inspection of capsules were used for packing. Leak test failure observed during in process check which was because of improper foil tightness and may be extra sealing pressure applied. This was machine setting issue to this batch only. This is isolated incident.
    After correct machine setting. Leak test compliance ensured, and no risk identified to pack integrity.
    SOP Ref. No. : CQ/003 Page 3 of 3
    Format No.: CQ/003/F-03
  8. Preventive Action:
     Instructed concerned to have more vigilant during machine setting and proper sealing pressure and foil tightness need to be ensured. Retraining needs to be imparted to concern on machine setting and similar incident are to be monitored for next three month.
    Prepared By: Reviewed By: Approved By

(YOGESH NARKHEDE) #57

Annexure - III
Investigation Report Format I/PR/18/025
Purpose:
Purpose of this investigation is to identify the root cause and to determine appropriate corrective and preventive actions for machine stoppage during drying activity of product Fluoxetine Tablets USP 60 mg Batch number: 12218002 Lot number 2.
Scope:
The Scope of this investigation is applicable to
Product name – Fluoxetine Tablets USP 60 mg.
Batch No. – 12218002
Batch Size – 54.154 kg equivalent to 150000 Tablets
Manufacturing date: Feb.2018
Expiry date: Jan.2020
Background:
The product Fluoxetine Tablets USP 60 mg is manufactured at Inventia Healthcare Pvt. Ltd for the US market.
This product is manufactured using Rapid mixer granulator 150L for granulation and FBE -125L for drying and lubrication of granules in Cage blender 250L,29 station compression machine (Korsch 400 XL) for compression and Auto coater 800 for coating activity.
Manufacturing process of this batch was carried out up to drying in two lots i.e. Granulation in two lots in Rapid mixer Granulator 150L and lot wise drying of granules in Fluidized bed equipment 125L.
After granulation of lot-2, it was transferred to FBE 125 for drying. Setting of drying parameters was done as defined in BMR.

  1. Drying activity was initiated and after about 60 minutes of drying, broken bag detector alarm was generated (Alarm was received at 18:08Hrs.) and machine stopped. Activity was stopped and immediately intimated to engineering. Engineering person cleaned the BBD sensor and drying activity was continued at 18:20 Hrs. Presence of powder at BBD sensor was checked on service floor and no such observation was noted.
  2. Machine stopped again at 18:37 Hrs. due to the same alarm for BBD sensor. Breakdown intimation was raised. Material was unloaded and weight of partially dried granules was checked. Loss on drying of partially dried granules was 12.08 % w/w and weight of unloaded partially dried granules was 29.82 kg.
    Engineering person attended the breakdown & after successful machine trial, further drying activity was continued from 23.45 Hrs. and completed on 23/Feb/2018, 00:19 Hrs.
    Total drying time for lot -2 of this batch was 70 minutes and Loss on drying was observed 2.35 % w/w. The recommended limit for drying time in BMR is 60 to 90 min and limit for loss on drying is NMT 2.5 % w/w.
    There was no impact on LOD which was the critical attribute. The product temperature, which is the associated critical process parameter, did not exceed the upper limit. All other critical attributes and critical process parameters were within specified limits.
    SOP Ref. No. : CQ/003 Page 2 of 6
    Format No.: CQ/003/F-03
    This report aims to identify root cause and propose actions for the observed stoppage during drying activity of lot -2 of batch under investigation and assess the impact of stoppage during drying activity on the final quality of product.
    Investigation:
  3. Investigation related to process ( Drying Process) :
    1.1 Drying activity of Lot 2 was initiated on FBE 125L (PR036) on 22/Feb/2018 at 17:07 Hrs. Set & actual drying parameters recorded in BMR are as mentioned below;
    Sr.
    No.
    Parameter
    UOM
    Set parameter
    Actual observation
    Lot 2
    01
    Inlet air temperature
    °C
    65 ±10°C
    70
    02
    Product temperature
    °C
    25 to 50°C
    40
    03
    Exhaust air temperature
    °C
    25 to 55 °C
    46
    04
    Total Drying time
    Min.
    60 to 90 minutes
    70
    1.2 Prior to initiation of drying activity, FBE bag and FBE bowl sieve integrity was checked and found satisfactory.
    1.3 Sequence of alarm events during drying activity is as mentioned below;
    Sr.No.
    Drying activity details
    Alarm details time
    Remark
    01
    Drying was initiated on 22/Feb/2018 at 17:07 Hrs.
    18:08 Hrs.
    After about 60 minutes of drying, the first alarm was generated for BBD sensor.
    Engineering was informed and BBD sensor was verified for presence of powder and no powder was observed.
    Concerned engineering person attended the observation and BBD sensor was checked, cleaned and again fitted. After cleaning of BBD sensor, drying was continued.
    02
    Drying continued on 22/Feb/2018 from 18:20Hrs.
    18:37Hrs.
    After total 87 minutes of drying and next alarm for BBD sensor was generated. Breakdown was initiated.
    This was attended by engineering and BBD sensor was cleaned again, fitting of BBD sensor was ensured correctly. FBE bag fitting was checked and found satisfactory. % exhaust flap was opened to 100 % and then FBE trial was taken and
    SOP Ref. No. : CQ/003 Page 3 of 6
    Format No.: CQ/003/F-03
    Sr.No.
    Drying activity details
    Alarm details time
    Remark
    after 20 minutes observation, FBE was taken for drying activity.
    Drying activity was reinitiated on 23:45Hrs. and completed on 00:19 Hrs.
    1.4 Drying activity was completed by ensuring intermittent raking as per BMR instruction to ensure proper fluidization. Although drying activity was completed within the defined time i.e. 70 minutes (60 to 90 minutes) and no excursion was observed in drying process parameters and Loss on drying of this lot was observed 2.35 % w/w which is well within specified limit (NMT 2.5 % w/w), evaluation was carried out to access the impact of the stoppage of 5 hrs. 08 minutes on the product quality.
    Evaluation:
    Drying activity was stopped intermittently because of broken bag detection alarms. As an action, BBD sensor was cleaned and exhaust flap was opened to 100 % and based on satisfactory machine trial, drying activity was continued. This breakdowns does not have any impact on drying process and drying of lot-2 under investigation was completed within the recommended drying time, although the holding time was 5 hrs.
    Loss on drying of partially dried granules at the time of breakdown was observed 12.08%. This material was unloaded and weight of granules was checked and unloaded material was kept in closed condition HDPE container in the area itself for 5 Hrs.08 min. There is no risk of contamination due to any extraneous material.
    No impact as partial drying was done and there were no lumps, drying was satisfactory carried out and further stages of sizing, blending/lubrication were carried out successfully. There were no abnormal observations during compression; batch compression completed at specified speed. Compression stage parameters were observed complying with BMR limits. Tablet quality was satisfactory with respect to visual appearance.
  4. Investigation related to equipment and measurement:
    2.1. The equipment i.e. RMG 150L and FBE 125 along with other equipment like co mill and sifter were in qualified status and calibrations were in place.
    2.2. Broken bag detector sensor is mounted on exhaust pipe /duct of equipment FBE125. Broken bag detector sensor comprises of sensor, electronic control unit and connecting cable. Sensor is made up of SS316L.
    2.3. Principle: BBD sensor works based on the phenomenon of charge transfer when moving particles come in contact with the sensor. This charge transfer is directly proportional to mass flow rate (Solid flow rate). % of solid flow monitor value is fixed value/Set value in HMI of FBE. In this case it was set as 40 %. If actual solid flow monitor value goes
    SOP Ref. No. : CQ/003 Page 4 of 6
    Format No.: CQ/003/F-03
    beyond the specified set value for more than 3 second, then machine generated BBD failure alarm and drying operation is stopped.
    2.4. After observing alarm of BBD, sensor was cleaned. Sensor mounting was checked and found correct. BBD alarm was again generated and hence again sensor was cleaned, % exhaust flap was 100 % open and empty trial was taken and found satisfactory.
    2.5. During investigation, finger bag and its fitting was found correct. No leakage or rupture observed. BBD sensor mounting was observed correct. Weight of dried granules was found satisfactory and there were no loss of material. During drying, fine particles may come in contact with BBD sensor and alarm can be generated.
    Evaluation:
    BBD sensor is installed to give alarm and stop the drying activity if there is particles come in contact with it. During drying activity BBD sensor alarm was generated and however there was no material loss observed. Other drying parameters and drying time was observed within the defined BMR parameters.
  5. Investigation related to personnel:
    3.1 Involved person in drying activity are trained and competent for granulation and drying activity. There was no manual intervention leading to alarm generation.
  6. Investigation related to environment:
    Temperature, humidity conditions in manufacturing areas were found to be well within specified limits of 19 to 27 °C and 40 to 65% RH and are not related to alarm generation.
  7. Investigation related to material:
    All materials used in the manufacturing were analyzed and approved by QC prior to manufacturing and are not related to alarm generation.
    Root Cause:
    During investigation finger bag and its fitting was found correct. No leakage or rupture to finger bag was observed. BBD sensor mounting was observed correct. Weight of dried granules was found satisfactory and there was no loss of material. May be because of fine particles were in contact with BBD sensor during drying activity and this deposition of fines can happen due to material sticking to the sensor immediately after moisture deposition on sensor during drying. This may happen occasionally and no risk to product as long as process was completed within specified time. Till verification of observed alarm partially dried material was kept in closed condition.
    Root cause Category:
    Equipment failure: Mechanical
    Corrective Action:
  8. BBD sensor cleaned and BBD sensor mounting verified.
  9. % exhaust flap was 100 % opened and trial was taken and found satisfactory.
  10. Batch will be released based on the review of finished product analysis result along with results of MLT of partially and fully dried granules.
    SOP Ref. No. : CQ/003 Page 5 of 6
    Format No.: CQ/003/F-03
    Risk Analysis:
    Loss on drying of partially dried granules at the time of breakdown was observed 12.08 %w/w. This material was unloaded in HDPE container in the area itself, weighed and kept in closed condition for 5 Hrs.08 min. There is no risk of any extraneous contamination however quality of granules and microbial load are the 2 potentially impacted criteria.
  11. Quality of granules:
    No impact as partial drying was done and there were no lumps, drying was satisfactory carried out and further stages of sizing, blending/lubrication were carried out successfully. There were no abnormal observation during compression; batch compression completed at specified speed. Compression parameters were observed within BMR limits.
  12. Risk of microbial growth: Risk of microbial growth: The LOD at the time stoppage was 12.08% hence sample of partially and fully dried granules were withdrawn for microbial limit test.Microbial testing on partially and fully dried granules was done and found complying with specification and results as below;
    Sr.No.
    Test
    Limit
    Observed results of partially dried granules
    Observed reading of Fully dried granules
    01
    Total Aerobic Microbial Count/
    Total Aerobic Viable Count
    Not more than
    1000 cfu/g
    Less than 100 cfu/g
    Less than 100 cfu/g
    02
    Total combined Yeasts and Mould
    Count/Total Fungal Count
    Not more than
    100 cfu/g
    Less than 100 cfu/g
    Less than 100 cfu/g
    TEST FOR SPECIFIED MICROORGANISMS
    03
    Escherichia coli (per gm)
    Should be absent
    Absent
    Absent
    04
    Salmonella spps. (per 10 gm)
    Should be absent
    Absent
    Absent
    05
    Staphylococcus aureus (per gm)
    Should be absent
    Absent
    Absent
    06
    Pseudomonas aeruginosa (per gm)
    Should be absent
    Absent
    Absent
    07
    Shigella boydii (per 10 gm)
    Should be absent
    Absent
    Absent
    Based on this there is no risk of microbial contamination.
    SOP Ref. No. : CQ/003 Page 6 of 6
    Format No.: CQ/003/F-03
    Preventive Action:
  13. BBD sensor are installed to identify if any leakage during drying activity and to avoid material loss because of rupture of finger bag and stop the machine immediately. Machine worked as intended hence no preventive action suggested.
    Prepared

(YOGESH NARKHEDE) #58

Annexure - III
Investigation Report Format I/PR/18/010
Purpose:
Purpose of this investigation is to identify the root cause and to determine appropriate corrective and preventive actions for machine stoppage during drying activity of product Metformin Hydrochloride Extended Release Tablets USP 500 mg, batch number SAN18021 Lot number 1.
Scope:
The Scope of this investigation is applicable to
Product name – Metformin Hydrochloride Extended Release Tablets USP 500 mg.
Batch No. – SAN18021
Batch Size – 855.625 kg =925000 tablets
Manufacturing date: Jan.2018
Expiry date: Dec.2019
Background:
The product Metformin Hydrochloride Extended Release Tablets USP 500 mg is manufactured at Inventia Healthcare Pvt. Ltd for the US market, client Sandoz being one of the marketing partners.
This product is manufactured using Rapid mixer granulator 1200L for granulation and Fluidized bed drier 1300L for drying, along with Co-mill fitted with 1.5 mm screen for milling of granules and Octagonal blender 2000L for lubrication of granules,Sejong compression machine (53 station) for compression and tablet inspection on Automatic tablet inspection machine (Enclony).
Manufacturing process of this batch was carried out up to drying in two lots i.e. Granulation in two lots in Rapid mixer Granulator 1200L and drying of granules in two lots in Fluidized bed equipment 1300L. Lot size for granulation and drying was 425.501 kg.
After granulation lot-1 was transferred to FBD 1300 for drying activity. Drying parameters setting was done as defined in BMR.

  1. Drying activity was initiated and after about 13 minutes of drying alarm was received (Alarm was received at 14:43 Hrs.), The alarm was for differential pressure across bowl observed high, bowl was removed and raking was done. Again drying activity was initiated at 14:52 Hrs.
  2. About after 26 minutes of drying at 15:05 Hrs. machine was stopped at 15:05 Hrs. which was because PLC touch screen of FBD 1300 was not working. Hence breakdown intimation raised, the functioning of PLC parameter was verified with help of external mouse connection and further drying was continued.
  3. After rectification of PLC touch screen, empty trial was taken, during this trial alarm of FBD blower trip was received. New breakdown intimation was initiated. After rectification of observed breakdown and by ensuring raking of partially dried granules & drying was completed at 21:05 Hrs.
    SOP Ref. No. : CQ/003 Page 2 of 7
    Format No.: CQ/003/F-03
    Total drying time for lot -1 of this batch was observed 66 minutes and loss on drying was observed 2.98 % w/w. The recommended limit for drying time in BMR is 45 to 100 min and limit for loss on drying is 2.5 to 3.2 % w/w.
    There was no impact on LOD which was the critical attribute. The product temperature, which is the associated critical process parameter, did not exceed the upper limit. All other critical attributes and critical process parameters were within specified limits.
    This report aims to identify root cause and propose actions for the observed stoppage during drying activity of lot -1 of batch under investigation and assess the impact of stoppage during drying activity on the final quality of product.
    Investigation:
  4. Investigation related to process ( Drying Process) :
    1.1 After granulation, drying activity of Lot 1 was initiated on FBD 1300L.Line clearance was ensured prior to initiation of activity.
    1.2 Drying activity of Lot -1 was initiated on 22/Jan/2018 at 14:30 Hrs. Set & actual drying parameters recorded in BMR are as mentioned below;
    Sr.
    No.
    Parameter
    UOM
    Set parameter
    Actual Lot 1
    01
    Inlet air temperature
    °C
    90°C±10°C
    90
    02
    Product temperature
    °C
    40 to 55 °C
    50
    03
    Exhaust air temperature
    °C
    35 to 55 °C
    42 to 45
    04
    Air volume (initial )
    CFM
    Minimum 3500
    5335
    05
    Blower speed (Drive inlet % )
    %
    99 to 70
    99 to 70
    06
    Bag shaking interval
    min
    2
    2
    07
    Bag shaking time
    Sec
    10
    10
    08
    Dew point
    °C
    5
    5
    1.3 Sequence of alarm event during drying activity as mentioned below;
    Sr.No.
    Drying activity details
    Alarm details time
    Remark
    01
    Drying was initiated on 22/Jan/2018 at 14:30 Hrs.
    14:43 Hrs.
    About 13 minutes drying was completed and first alarm received for differential pressure across bowl was high. Hence bowl was removed, raking was done and then drying was started.
    Observed high differential pressure across bowl may be because of chocking of bowl
    SOP Ref. No. : CQ/003 Page 3 of 7
    Format No.: CQ/003/F-03
    Sr.No.
    Drying activity details
    Alarm details time
    Remark
    gill plate. Instruction for intermittent raking is mentioned in BMR and after getting alarm for differential pressure across bowl, raking was done.
    02
    Drying was initiated on 22/Jan/2018 at 14:52 Hrs.
    14:52 Hrs.
    About 26 minutes drying was done and again breakdown was initiated as PLC touch screen was not working.IT and engineering attended the observed breakdown and external mouse connection was provided & empty trial run of FBD was taken.
    During empty trial run of FBD, blower was tripped.
    This was attended by engineering and it was observed that there was a loose connection to the VFD feedback wire. The connection to the PLC was done and again trial was taken and was found satisfactory.
    1.4 After rectification and about 05 hours and 08 minutes stoppage, drying activity was initiated at 20:13 Hrs. and by ensuring intermittent raking as per BMR instruction to ensure proper fluidization. Although drying activity was completed within the defined time i.e. 66 minutes (45 to 100 recommended) and no excursion was observed in drying process parameters and Loss on drying of first lot was observed 2.98 % w/w which is well within specified limit (2.5 to 3.2 % w/w).Evaluation was carried out to access the impact of the stoppage of 5 hrs. 08 minutes on the product quality.
    Evaluation:
    Drying activity was stopped intermittently because of observed breakdown to PLC touch screen and because of VFD feedback wire loose connection in PLC. These observed breakdown does not have any impact drying process and drying of lot under investigation was completed within the recommended drying time.
    Loss on drying of partially dried granules at the time of breakdown was observed 13.99 %. This material was held in bowl in the area itself in closed condition for 5 Hrs.08 min. There is no risk of any extraneous material.
    No impact as partial drying was done and there were no lumps, drying was satisfactory carried out and further stages of sizing, blending/lubrication were carried out successfully. There were no observation during compression batch compression completed as specified speed. Compression stage parameters were observed complying with BMR limits. Related substance testing compliance was ensured during QC testing.
    SOP Ref. No. : CQ/003 Page 4 of 7
    Format No.: CQ/003/F-03
    Risk of microbial growth: The LOD at the time stoppage was 13 % which indicate water activity required for growth of microorganism was very low. Further shear forces of compression are known to reduce microbial load.
  5. Investigation related to equipment and measurement:
    2.1. The equipment i.e. RMG 1200 and FBE 1300 along with other equipment like co mill and sifters and peristaltic pump were in qualified status and calibrations were in place.
    2.2. Although there is no direct product impact based on 2.1, evaluation was extended to understand sequential breakdown during drying of this batch. Following are the observations prior to start of process.
    Sr.No.
    Breakdown details
    Start time and end time
    Remark
    01
    After cleaning and product changeover PLC of FBD was not working on 22/Jan/2018 at 00 Hrs. 05 min.
    22/Jan/2018 00:05 Hrs. to 05:25 Hrs.
    Prior to initiation of batch under investigation there was product to product changeover and cleaning activity was done.
    PLC display touch screen was not working and moisture observed on MMI/HMI. Same was dried with help of hot air blower and checked found working.
    MMI/HMI pendent has top cable entry due to which during cleaning activity/product change over there may possibility of ingress of moisture.
    As per procedure instruction for shrink wrapping to MMI/HMI screen is mentioned and same is in practice however in this batch chances of ingress of moisture may occurred because of shrink wrapping to MMI/HMI screen was not done properly. Improper shrink wrapping may done because of MMI/HMI pendant having cable entry from top side.
    Action plan:
  6. During shrink wrapping to MMI/HMI screen care has be taken however this was isolated incident. After this observation, immediately instructed concerned to ensure proper shrink wrapping to MMI/HMI screen to avoid ingress of moisture during cleaning/product changeover.
  7. To avoid in grace of moisture during changeover MMI/HMI pendant will be
    SOP Ref. No. : CQ/003 Page 5 of 7
    Format No.: CQ/003/F-03
    Sr.No.
    Breakdown details
    Start time and end time
    Remark
    modified to have cable entry from bottom side.
    02
    Second breakdown received i.e. blower not starting on 22/Jan/2018 08:30 Hrs.
    22/Jan/2018 08:30 Hrs. and completed on 22/Jan/2018, 12:26 Hrs.
    All electric connection were checked and machine interlock were checked. After resetting the system and then trial taken. Same was found satisfactory.
    Concerned engineering technician has verified all electrical connection with respect to blower and may during verification there may chance of some of wiring connection may not done properly and connection may remained loose, which further leads to observed breakdown to FBD blower during batch run.
    Action plan :
  8. Observed loose connection of VFD feedback wire is rectified and then FBD empty trial was taken and drying activity of lot -1 was completed.
  9. Instructed to concerned engineering technician to have more vigilance while attending the breakdown.
    Evaluation:
    Observed breakdown to PLC of FBD may be cause of improper /loose connection of VFD feed back wire which may remain loose while attending the initial breakdowns.
    Also while product changeover /cleaning of equipment activity, prior care was not taken and moisture may in graces in MMI of equipment.
  10. Investigation related to personnel:
    3.1 Involved person in drying activity are trained and competent on granulation and drying activity.
    3.2 Involved engineering person who attend the breakdown maintenance is qualified and competent. At the time of rectification of PLC breakdown/ FBD blower functioning verification and several electric connections were verified and connected, there may be possibility of VFD feedback to PLC connection was loose and not connected properly.
    3.3 Instructed to engineering technician to have more attention and vigilance while attending the breakdown.
  11. Investigation related to environment:
    Temperature, humidity conditions in manufacturing areas were found to be well within specified limits of 19 to 27 deg C and 40 to 65% RH.
    SOP Ref. No. : CQ/003 Page 6 of 7
    Format No.: CQ/003/F-03
  12. Investigation related to material:
    All materials used in the manufacturing were analyzed and approved by QC prior to manufacturing.
    Root Cause:
    Observed breakdown to PLC of FBD may be cause of improper /loose connection of VFD feedback wire which may remain loose while attending the initial breakdown.
    Also while product changeover /cleaning of equipment activity, prior care was not taken and moisture may in graces in MMI/HMI of equipment.
    Corrective Action:
  13. Observed loose connection of VFD feedback wire is rectified and then FBD empty trial was taken and drying activity of lot -1 was completed.
  14. For operation of PLC screen, mouse is attached.
  15. Instructed to concerned engineering technician to have more vigilance while attending the breakdown.
  16. Batch will be release based on the review of finished product analysis result.
    Risk Analysis:
    Loss on drying of partially dried granules at the time of breakdown was observed 13.99 %. This material was held in bowl in the area itself in closed condition for 5 Hrs.08 min. There is no risk of any extraneous material however quality of granules and microbial load are the 2 potential impacted criteria.
  17. Quality of granules:
    No impact as partial drying was done and there were no lumps, drying was satisfactory carried out and further stages of sizing, blending/lubrication were carried out successfully. There were no observation during compression batch compression completed as specified speed. Compression stage parameters were observed complying with BMR limits. Related substance testing compliance was ensured during QC testing.
  18. Risk of microbial growth: The LOD at the time stoppage was 13.99 % which indicate water activity required for growth of microorganism was very low. Further shear forces of compression are known to reduce microbial load.
    Based on this there is no risk of microbial contamination. However Microbial testing of batch under investigation on control sample will be ensure concurrently.
    SOP Ref. No. : CQ/003 Page 7 of 7
    Format No.: CQ/003/F-03
    Preventive Action:
  19. For observed PLC touch screen rectification, matter will be referred to OEM to rectify the same.
  20. Possibility of modification of MMI/HMI pendant will be checked to have cable entry from bottom side.
    Prepared By:

(YOGESH NARKHEDE) #59

Annexure III
Investigation Report Format I/PR/18/001
Format No.: CQ/003/F-03 Page 1 of 2
Purpose:
This report prepared against (I/PR/18/001) to find out corrective and preventive action against the observed Blister Inspection System failure (Equipment I.D- PR158).
Scope:
Packing activity of below mentioned product/batches were taken in PP07 area on Elmach blister pack machine;

  1. Telmisartan Tablet USP 20 mg B.No. 06117005 and 06117006.
  2. Batches were taken under deviation list attached to Deviation (D/PR/17/025) (Refer list attached to deviation).
  3. Batches taken under deviation list attached to Incident (I/PR/18/001).
    Investigation:
  4. Product Telmisartan Tablet USP 20 mg B.No. 06117005 batch packing activity was initiated on Elmach Equipment I.D. PR325. Packing operation started on 15/Dec/2017, at the time challenge test operator observed that BIS system is not working properly i.e. Windows could not start because of the alarm received as file is missing or corrupt. Hence blistering was not done breakdown was raised. Batch was kept aside.
  5. Below breakdown observed and its status.
    Sr.No
    Date
    Product Name
    Breakdown Description
    Status
    1
    16/Dec/2017
    Telmisartan Tablet USP 20 mg B.No. 06117005
    BIS system was not working due to missing of file /system32/ntoskron/exc,
    OS is reinstalled Breakdown closed on 19/Dec/2017
    2
    26/Dec/2017
    Ziglim M1 B.No. 407L003
    I and II track good and III track blister was rejected continuously. (Incident I/PR/18/001) raised.
    9 th track in the system was not activated M/S Jekson issue was resolved
    3
    16/Jan/2018
    Ziglim M1 B.No. 408A001
    Out of 09 empty blister, 8 blister were rejected and 1 blister accepted
    service engineer checked and found wrong software output registry
    On 16/Dec/2017 to 17/Dec/2017, no batch was taken on Elmach packing machine.
  6. Deviation (D/PR/17/027) was raised on 18/Dec/2017 saying that during machine setting trial hence batches were packed without BIS system. Under this total 04 batches were completed.
    SOP Ref.No.:CQ/003
    Annexure III
    Investigation Report Format I/PR/18/001
    Format No.: CQ/003/F-03 Page 2 of 2
  7. Breakdown was closed on (19/Dec/207) saying that trial found satisfactory hence BIS system challenged test performed and requalification required.
  8. Recording of performed checks on equipment operation and software operation BIS was performed on 22/Dec/2017 for Product Glyciphage G1 B.No.IA17044 challenge test of BIS found satisfactory.
  9. Incident (I/PR/18/001) was raised on 02/Jan/2018 for observation of BIS system i.e. out of three track one track was not operating properly, it was continuously rejecting the good blister. There was error observed on HMI i.e. A1-7000 on motion controller CPU & communication error on HMI hence to find out cause of BIS system failure breakdown was raised.
  10. From 08/Jan/2018 to 16/Jan/2018 batches were packed under BIS system.
  11. Production officer raised the breakdown intimation slip to rectify the problem.
  12. Service engineer Jekson visited on 10/Feb/2018 to monitored Ziglim M2 B.No.408B001 and Ziglim M2 B.No.408B002 to solve the issue of Track no. 09 continuously rejection problem service engineer checked and found wrong software output registry, this was not checked at previous breakdown when OS was installed.
  13. Service engineered edited file in software output and all track challenged test was performed and found satisfactory.
    Corrective action:
  14. Batches of Ziglim M2 B.No.408B001 and Ziglim M2 B.No.408B002 batch packing activity monitored critically.
  15. Service engineer Jekson corrected output registry.
  16. Challenged test was found satisfactory.
    Risk Analysis:
    All the batches was manufactured under deviation as all batches AQL was performed hence no risk to product quality. After this corrected output registry challenged test found satisfactory and there is no impact on product quality
    Root cause:
    Machine/Equipment: Software problem
    Preventive action:
    Activity of installation of OS in any system IT person need to verify the output registry to prevent such re-occurrence.
    Prepared by: Checked by: Approved

(YOGESH NARKHEDE) #60


(YOGESH NARKHEDE) #61