capacity improvement bulk drug productqcin.org/nbqp/dlshah-award/pdf/2016/lupin limited.pdf · sop...
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Project leader (Black Belt) : Paramjeet Singh(Plant In-Charge CV-4)
Project Sponsor : Jayesh Patel(Manager – Operational Excellence- Black Belt)
Program Champion : K C Sharma(VP and Site head)
Disha Program Leader : Pankaj Agarwal(VP – OpEx)
Capacity Improvementof
Bulk drug product
1
Lupin Limited: Entry for QCI
• Project Leader: Paramjeet Singh• Lupin Limited, 198-202, New Industrial Area no 2, Mandideep 462046, District: Raisen, Madhya Pradesh• Phone: +91 7480 410396, Mobile :8818908285• Mail: paramjeetsingh@lupin.com
• Project Sponcer: Jayesh Patel• Lupin Limited, 198-202, New Industrial Area no 2, Mandideep 462046, District: Raisen, Madhya Pradesh• Phone: +91 7480 410400, Mobile :9617777485• Mail: jayeshbpatel@lupin.com
• Site Head: K.C.Sharma• Lupin Limited, 198-202, New Industrial Area no 2, Mandideep 462046, District: Raisen, Madhya Pradesh• Phone: +91 7480 410422, Mobile :9617770422• Mail: Krishancsharma@lupin.com
• Program Leader: Pankaj Agarwal• Lupin Ltd, 159 CST Road, Kalina, Santacruz (E)• Mumbai 400 098. India, Phone: +91 22 6640 2701• Fax: +91 22 6640 2051• Mail: pankajagarwal1@lupin.com
2
Contact information
Build a sustainable operating model for improving and sustaining profitability by developing continuousimprovement capabilities within Lupin
• Kicked off in 2012 at two pilot sites, has covered all sites of Lupin in India• Top driven – Steering committee chaired by MD• Uses Lean Six Sigma approach for continuous process improvement• A pool of trained …….. Black Belts and 72 Green Belts have been created• Saved over INR 70 Cr since inception of the program
3
DISHA – Operational Excellence Program at -MDP
• Project Title: Capacity Improvement of a bulk drug product• Duration: Oct-14 to March-15• Project Leader: Paramjeet Singh• This is a large plant with 12 stages spread over 3 blocks, 40 reactors, 7 centrifuge, 5 WFE, 4 IEC, 6 dryers ,1 RO
unit & Hydrogenation plant• Plant is operated by 97 Permanent and 92 contract workers- 3 shifts 7 days a week• This project followed LEAN approach , wherever required DMAIC tools were also used• Detailed VSM ( Value Stream Map) was made with cycle time at each step• Based on the cycle time at each step and TAKT time required bottleneck operations were identified• Bottlenecks were identified through a three level drilldown
– Step wise capacity– Equipment wise– Process wise
• Each bottleneck was discussed in detail with Process Development and Production to identify VA/NVA.• Pilot was done with identified themes• Shortlisted ideas were implemented and sustained over three months from Mar to May.• Financial validation of the project
* The name of the product is NOTdisclosed due to confidentiality
4
Executive Summary of the Project
Business Case Scope Increasing the plant throughput from 10.0 to 11.0 TPM will
help in meeting the customer demand as well as deliver usa net profit of 2.69 Cr/Annum.
All in-house manufacturing steps are in scope of theproject
Goal Statement Increase the takt rate of bulk drug plant from 10 TPM to 11TPM@ 26 days
Project Team Project Plan Mr. Bhupendra Singh Mr. Priyesh chokade Mr. Ranjit sitole & Vasu babu Mr. Shahanawaz & Suyeb Mr. Vishal Pandey Mr. Radheshyam Gothwad Mr. Naresh Lodha
Mr. Dr. Venu Mr. Alkesh patel Mr. Sunil Mishra Mr. Mohit Gupta Mr. Ruby Sharma Mr. Amit Saxena Mr. Sameer D.
Tollgate ScheduledDefine: 25/10/14Measure: 25/11/14Analyze: 22/12/14Improve: 25/01/15Control: 20/02/15
API Throughput Improvement
Project Approach
Step wise capacity
Equipmentwise
capacityOperationwise study
• Steps having capacity is >= 11 MT are removed from scope• Reduced 3 steps from scope
• Equipment capacity is >= 11 MT are removed from scope• Reduced 12 equipment's from scope
Detailed VSM exercise was done to identify the losses
Idea generation to reducethe time cycle
Pilot with identifiedsolution theme
Full scaleimplementation
Control andsustenance plan
Process flow diagram & Step wise evaluation
Step- 1 Outsourced
Step- 2
Step- 3 Outsourced
Step-5
Step- 6
Step- 7
Step- 8
Step- 9
Step- 10 Step- 11 Step- 12
• LIS-2, LIS-5 & LIS-6 steps is already having 11.0 MT capacity hencenot need to work further.
• LIS-7 to LIS-12 steps needs to increase the capacity form 10 to 11MT/month
• LIS-1 & LIS-3 both are out of scope as outsourced
10.1
10.3 10
10.3
10.1
10.3
11.4
14.5 11
Step-12 Step-11 Step-10 Step-9 Step-8 Step-7 Step-6 Step-5 Step-2
Step wise capacity MT/Month Currrent takt rate MT/Month Target takt rate MT/Month
Step details are further drilldown to equipmentdetails (1/2)
10.8
10.3 10.3
R-19-1006 R-19-705 R-19-1007
10.3 10.1 12.217.2
10.2
R-19-806 R-19-807 R-19-704 R-19-701 R-19-809
10.3
27.5
14.9
R-20-1003 R-19-1004 PF-20-1001
14.3 10.7 10.7 10.3 10.0 11.3
R-20-1005 /1006 ANFD-06-001 WFE19-1002 R -19-1008 R -19-1009 R-19-1010
LIS-10
LIS-7 LIS-8 LIS-9
• Equipment wise evaluation provided the Key equipment list where time cycle needs to be reduced• 11 Equipment's capacity needs to be improved at LIS-7 to LIS-10 stage
Step details are further drilldown to equipmentdetails (2/2)
10.7 11.4 11.213.7
10.4 10.3 11.5 10.6
17.4
IEC-03/04/05 V-19-1139 R.O-19-1101 R-19-1101 WFE-19-1101 R-19-1105 R-19-1103/4 CF-1102/602 RVD-19-1103
10.8 10.2 10.1 10.2
27.6
10.7
R-19-1102 WFE-19-1201 R-19-1205/6/7 CF-19-1202/1101 M-19-1201 VTD-19-1202/1204
LIS-11
LIS-12
• Equipment wise evaluation provided the Key equipment list where time cycle needs to be reduced• 9 Equipment's capacity needs to be improved at LIS-11 & LIS-12 stage
Summary for scope drilldown
Sr.No Step
1 LIS-2
2 LIS-5
3 LIS-6
4 LIS-7
5 LIS-8
6 LIS-9
7 LIS-10
8 LIS-11
9 LIS-12
Sr.No Step
1 LIS-7
2 LIS-8
3 LIS-9
4 LIS-10
5 LIS-11
6 LIS-12
LIS-7 LIS-8R-19-1006 R-19-806 R-19-701R-19-705 R-19-807 R-19-809R-19-1007 R-19-704LIS-9 LIS-10R-20-1003 R-20-1005/6 WFE-19-1002R-20-1004 R-19-1008 R-19-1009PF-20-1001 ANFD-06-001 R-19-1010
LIS-11IEC-03/04/05 WFE-19-1101 CF-19-1102/602V-19-1139 R-19-1105 RVD-19-1103RO-19-1101 R-19-1103/04 R-19-1101
LIS-12R-19-1102 WFE-19-1202 R-19-1205/6/7CF-19-1201 CF-19-1102 M-19-1201VTD-19-1202 VTD-19-1204
LIS-7 LIS-8R-19-1006 R-19-806R-19-705 R-19-807R-19-1007 R-19-809
LIS-9 LIS-10R-20-1003 ANFD-06-001
WFE-19-1002R-19-1008/09
LIS-11IEC-03/04/05 WFE-19-1101CF-1102/602 R-19-1105
LIS-12R-19-1102 WFE-19-1201CF-19-1201 CF-19-1102VTD-19-1202 VTD-19-1204R-19-1205/6/73 steps reduced from scope
12 equipment's are reduced from scope
Complete-VSMFocused VSM exercise carried out for LIS-7 to LIS-12 steps. To understand the process Identify Value added and Non-Value added activities Generate relevant ideas for cycle time reduction
R M
Order Planning ToPlant executive
Order Planning ToLot Incharge
Order Planning ToShift Incharge
ProductionPlanning & Control
Ware house
I
FIFO
RawMaterial
Order RequirementTo Production
ManagerProduction
Planning & Control
Forecast Monthly
I
Lotshifting
Lot Area
2 officer2 Operator6 Casuals
10
Sylilation & Condensation
7 Operator7 Casuals
14
Centrifuge
7/2 Officer14/2 Casuals 10
Milling
7/2 Officer7/2 Casuals 7
Drying
4/2 Officer14/2 Casuals 9
Hydrolysis
7/2 Officer7/2 Casuals 7
Precipitation
7/2 Officer7/2 Casuals 7
Sifting
4/2 Officer7/2 Casuals
5
FPP5 Operator6 Officer27 Casuals
38
I
ApprovedSolvent
ApprovedSolvent
ApprovedSolvent
I
Order Planning ToSolvent Rec Incharge
Lot 6Batches
SOP
VM
SRP Area
5 officer10 Operator7 Casuals
22Truck
SOP
VM
SOP
VM
SOP
VM
SOP
VM
SOP
VM
In Process QalityCheck IPQC
VM VM VM
SOP SOPSOP
Process Cycle Time(min)Value Added Time (minTAKT Rate (min)
7.23.16.5
P C TV A T
7.21.86.5TAKT Rate
P C TV A T
71.76.5TAKT Rate
P C TV A T
6.93
6.5TAKT Rate
P C TV A T
3.53
6.5TAKT Rate
P C TV A T
8.26
6.5TAKT Rate
P C TV A T
3.83
6.5TAKT time
11
Value stream mapping activity Effort’s• Took over 7-Days to complete ( 25 Hrs)
• 18 Meter chart paper used
• 27 members including PD lab, Process Engg. &
production.
• Identified all hidden factors & key parameters impacting
the process
Value stream mapping activity Effort’s• Took over 7-Days to complete ( 25 Hrs)
• 18 Meter chart paper used
• 27 members including PD lab, Process Engg. &
production.
• Identified all hidden factors & key parameters impacting
the process
Value Stream Map
Step-7 – Separate utility line provision
15
20
30
15
30
120
25
20
90
25
40
15
70
10
Reactor cleaning
Layer seperation
Settaling
Agitate & Cool
Toluene charging
Agitate & HPLC
K2CO3 add.
Charge TFAL & BCF
Agitate & Cooling
Charge sodiumcarbonate
Charge potablewater
R-19-1006
After modificationBefore modification
-20 brine header-20 brine header
R-19-1006• Total time of reactor is reduced to 380 min from 430 min and capacity increase from 10.8 to 12.2
MT/month
VSM• Vessel cooling time was
more then reactor. Solution theme:• Chilling time reduce by
separate -20 brine line toreactor & Agitated vessel
• Advance carbonate solutionpreparation
• Safety risk analysis done and static charge dissipation timereduced by considering following factors.
• SS reactor, Dip pipe in reactor, Toluene charged in water & toluenequantity
Put actual photo ofplant
Step-7 – Elimination of operation
130
100
140
60
20
30
2nd EA extraction
1st EA extraction
pH adjustment
EA charging &chilling
Transf. Aqu.Layer
R-19-705
2nd EA extractionRecycling
1st EA extraction Processed in next stage
Practice before project:• 2nd EA extraction was stored in
vessel and charged in next batch• Further cooling of 2nd EA layer
was done in reactor for pHadjustment
Practice after project:• 2nd EA extracted layer stored in
reactor and makeup with EA for1st extraction of 2nd batch
• EA charging& cooling time wasreduced to reduce the reactoroccupancy of R-19-705
R-19-705
60
60
200
200
190
265
180
620
30
40
225
450
Unloading
EA Makeup +Agitation &…
4th Dehydration
3rd Dehydration
Distillation
Dilution &Filtration
1st Dehydration
Concentrationof 4.0 batches
R-19-1007Concentration timereduce by increase ofutility line size ofcondenser
Filtration time reductionby increase of filtrationarea.
Chilling time reduce byreplacement of existingcooling water utilitywith chiller water.
Operationeliminated
Step-8 – Waiting time reduction
15
90
110
80
75
60
30
O/L Transferring
Water wash
1st Na2CO3 Wash
1st Na2CO3 Wash
Water wash
HCL Wash
RXN Masstransferring
R-19-807
40
25
60
400
30
800
30
10
30
15
720
Unloading
Methanolcharging
Cooling
Dehydration
M/C checking
WFE feeding +Flushing
Vacuumapplication
Waiting timereduced bysynchronization ofother reactors timei.e. Advance PROFpreparation
Batch to batch cleaningoperation removed
Statistic dissipationtime reduced
Na2Co3charging &agitationoperationclubbed
Waterchargingthroughwatermeter
R-19-809Utility linesize for H.W.& C.waterincreasedWFE flushingoperationremoved.
Cooling waterutility replacedwith chilledwater.
LI of vesselmodified .
20
30
30
40
75
35
75
0
20
20
60
Batch to Batchcleaning
RXN Masstransferring to R-
807
Sampling &Temp raise
PROF addn &Flushing
TEA addn &Flushing
PVCL addn &Flushing
Agitate & chill
R-19-807
Step-9 & 10A – Internal element to external
130
15
100
60
5
20
10
20
20
35
105
100
10
10
Filtration & Washing
H2 cutoff & Release
Hydrogen Maint
Hydrogen application
Agitator frequencyadj.
Pressure testing &evac.
Vessel flushing
Charge MeOH thenCBZPM
Reactor evac. &release
pd/c Charging &Settling
Reactor CleaningR-20-1003
Simultaneouschargingof MeOH& CBZPM
BeforeAfter
• Two time water filled in reactor (2.0 KL x 2)to remove the traces of MeOH & pd/c toprevent the fire during pd/c charging inreactor.
• Proposed to provide the additional 250 Litvessel for pd/c charging and this activitybecome offline
• Approx. 4KL/day effluent will be reduced.
• Two time water filled in reactor (2.0 KL x 2)to remove the traces of MeOH & pd/c toprevent the fire during pd/c charging inreactor.
• Proposed to provide the additional 250 Litvessel for pd/c charging and this activitybecome offline
• Approx. 4KL/day effluent will be reduced.
30
30
30
40
80
80
150
40
20
0
Cleaning
Unloading
2n Waterwash
1st Waterwash
II nd MeOHwash
I st MeOHwash
Filtration
ANFD filling
O2 checking& pressure…
ANFD-06-001
Operationremoved
R-19-1008 R-19-1009 R-19-1010
R-19-1008
R-19-1009
R-19-1010
Output
OutputOutput
OutputOutput
Operation Time Propose Remark
A/L,DCM charging & cooling 30 30 R-19-1009Timecycle-535Capacity10.0TPM
pH Adjustment 30 301st DCM extraction 60 602nd DCM extraction 60 60Water washing of DCM layers 65 65Hydrolysis with Caustic & Distillation 260 260Reactor cleaning 10RXN mass transferring to R-19-1010 20RXN mass received from R-19-1009 20 R-19-1009
Timecycle-475Capacity11.3TPM
Cooling & pH adjustment 110 110Temp raising 50 501st DCM wash 95 951st DCM wash 75 75Degassing 90 90Unloading and reactor flushing 20 20Batch to batch cleaning 15Total time cycle for proposed /reactor 473Capacity TPM 11.3
Step-10 – Transferring time eliminationBefore Project
After Project
Step-11 A – Distillation rate improvement
25
120
150
80
35
180
35
180
45
270
150
4020
240
90
35
Colum…
Water…
Hcl circulation
Water…
Unlaoding…
3rd elute
Unlaoding…
2nd elute
Unlaoding…
1st elution
Desalting &…
Drain Lisfree
TLC checking
LoadingIEC-1103/04/05 Time in min Capacity TPM
Operation Current Proposed Current Proposed
Vacuum Application 25 25 10.4 11.6Concentration 485 430Cleaning 30 30
Final solution theme implemented• H.W. line size increased with high capacity pump• Preheater installed to reduce the sensible heat load
in WFE.Unloading andwater washing timereduced byincrease of drainline size from 1” to1.5”. Time limitremoved for pHachieving
Pre- heater
Step-11 B –Reverse Breaking in Centrifuge
15
20
480
30
420
Batch to Batchcleaning
Reaction masstransferring
Distillation
WFE masscharging
R-19-1105
45
60
15
18015
35
30
30
120
30
0
15
Batch to batch cleaning
CFG unloading
Wet cake checking &Spining if required
Final spining
Spin the CFG for MLseperation
Slurry wash / Spray wash
Stickness checking
Spin the CFG for MLseperation
CFG feedingCF-19-1102/602• Separate H.W. line provided from Hot water
tank• New 3KL reactor installed in place of 1KL
reactor
• VFD installed with reverse breaking so CFGstopping time reduced by 15 minutes, sametime also reduced during CFG cleaningprocedure
• In case of spray wash CFG spinning time isnot needed
Step-12 – Additional equipment provision
15
20
480
30
420
Batch toBatch cleaning
Reactionmass
transferring
Distillation
WFE masscharging
WFE-19-1201
50
14030
60
60
60
30
30
30
Washing &Filtration
Filtration
Agitation
Cool & Carboncharging
Agitation
Charge CLIS &Poly bag flushing
Heating
Chrge purifiedwater
R-19-1102
15
80
60
15
85720
15
5
30420
30
50
20
360
15
Batch to…
CFG feeding
Agitate the…
Et-OH…
Cooling
Maintaining
Seeding +…
Charge…
Temp raising
Distillation…
WFE Mass…R-19-1205/06/07
CLIS chargingwith poly baginstead ofscoop
Additional WFEinstalled, whichwas idle
Utility andvapor line sizeincreased
Step-12 – Manual time reduction with increasedmanpower
45
60
570
25
45
100
45
80
30
45
510
Batch to batchcleaning
Unloading
Final spining
Spray wash
Wash MLseperation
Slurry wash
ML seperation
CFG feedingCFG-19-1101/1202
30
45
240
40
240
40
24050
15
35
30
30
Batch to batchcleaning
Unloading
Drying
2nd Distrubing
Drying
1st Distrubing
Drying
Loading &Vacuum apply.
VTD-19-1201/02
• Final spinning time reduced by60 min
• Unloading with bigger scoop• Reverse breaking system to
reduce the CFG stopping time
Manual operation timereduced with oneadditional casual pershift
21
Stage EquipmentTag
Existing ProposedTime Cycle Hr Capacity TPM Time Cycle Hr Capacity TPM
LIS-7R-19-1006 7.17 10.8 6.33 12.2R-19-705 7.50 10.3 6.83 11.3R-19-1007 29.58 10.3 25.17 12.2
LIS-8R-19-806 7.50 10.3 6.58 11.8R-19-807 7.67 10.1 6.67 11.6R-19-809 23.1 10.2 20.8 11.3
LIS-9 R-20-1003 8.67 10.3 7.83 11.4LIS-10A ANFD-06-001 8.30 10.7 7.80 11.4
LIS-10BWFE-19-1002 8.33 10.7 8.00 11.2R-19-1008 8.70 10.3 7.70 11.6R-19-1009 8.92 10.0 7.67 11.6
LIS-11AIEC-19-1103/4/5/6 8.72 10.7 8.50 11.0WFE-19-1101 9.00 10.4 8.08 11.6
LIS-11BR-19-1105 9.10 10.3 8.10 11.6CF-19-602/1102 8.80 10.6 8.10 11.6
LIS-12
R-19-1102 7.67 10.8 7.17 11.6WFE-19-1201 8.10 10.2 7.50 11.0R-19-1205/6/7 8.20 10.1 7.50 11.0CF-19-1101/1202 8.08 10.2 7.33 11.3VTD-19-1204/05 7.71 10.7 7.33 11.3
All step and equipment's capacity with proposed solution theme
22
Stage Baseline Plant Capacity TPM @ 26 days After Pilot plant Capacity TPM @ 26 days
LIS-7 10.3 11.30LIS-8 10.1 11.30LIS-9 10.3 11.40
LIS-10 10.0 11.20LIS-11 10.3 11.00LIS-12 10.1 11.00
11.3 11.3 11.4 11.2 11 11
9
10
11
12
LIS-7 LIS-8 LIS-9 LIS-10 LIS-11 LIS-12
Capacity TPMcapacity TPM Base line
Pilots
23
11.0
11.3
11.6
10.2
11.0
11.1
10.0
10.7
Apr'15 May'15 Jun'15 Jul'15 Aug'15 Sep'15 Oct'15 Nov'15
Actual Production Ton/Month
82.8
106.
0
67.0
3.7
47.4
52.5
20.1
51.6
Apr'15 May'15 Jun'15 Jul'15 Aug'15 Sep'15 Oct'15 Nov'15
Saving In Lakhs
Plant Shutdown
Operational & Financial metric
Financial Validation
MonthlyProcessDashboards
Financial Results Tracking
25
ProjectBaseLineYield
Signed-offcapacity Apr May Jun Jul Aug Sep Oct Nov
Lisinopril-Capacity 10 M T 11.00 MT 11.00
MT11.31MT
11.61MT
10.15MT
11.00MT 11.10 MT 10.04
MT 10.65 MT
Due toShutdown
RS Lacs Actual
ProductSigned-offSavings
TotalActualAchieved
TotalProjection
TotalExpected
Apr May Jun Jul Aug Sep Oct Nov
LisinoprilCapacity 568.07 431.13 211.62 642.74 82.83 105.99 67.03 3.68 47.39 52.48 20.10 51.64
Project sustains plan
Challenges faced
• At LIS-10,11 and 12 stage, during all distillation operations, thereare temp limit for RXN mass only
• Convince the QA for above change• Tried to increase the utility temp to reduce the distillation time
at Step-10/11/ and 12• Unknown impurity was increased at final stage hence this change
was not regularized• Batches with higher impurity were reprocessed at final stage with
approved reprocessing method & quality found normal
Process challenges in term of quality• Plant shutdown for modification , as higher market demand• All modification were done in one day with additional
manpower from Unit-1 and clubbed with periodic cleaning toreduce the down time
• Non availability of piping & fittings for modification due tohigher lead time of procurement & approved budget
• Piping and fittings were diverted from other projects.• QC analysis was addressed through proper planning and co-
ordination between QC and Plant
Execution challenges
0.04 0.07 0.08 0.12 0.36 12.5
4
6.2 78.3 8.5MT
Originally Plant is designed for 1 MT/Month andgradually increased up to 10MT.
To increase from 10MT to 11MT was a challenge interm of mindset as well as all the low hanging fruitswere already captured in earlier improvement.
0.04 0.07 0.08 0.12 0.361
2.5
4
6.27
8.3 8.5
1998 2013
MT
Originally Plant is designed for 1 MT/Month andgradually increased up to 10MT.
TO increase from 10MT to 11MT is a challenge in termof mindset as well as all the low hanging fruit wasalready captured in earlier improvement.
Impact of Higher Temperature hot water theme later on dropped
• On investigation it was
conclude that unknown
impurity cause by change
in utility hot water temp
set point 58°C from 68°C
in Lisinopril manufacturing
stages.
• Hence the change was
reverted back & there after
decreasing trend observed
from batch no. 50 onwards
Conclusion
645750433629221581
16
12
08
04
00
Observation
IndividualValue
_X=0.0107
UCL=0.0148
LCL=0.0066
Normal Step-12 Step-11-12 Step-10-11 Step-10 Normal
1
111
11
I Chart of Unknown imp by Increase Temp at various stage
People involvement:At all stages of project and primarily for thefollowing activities1. Creation of VSM2. Data collection for identification of VA & NVA3. Pilots4. Sustenance
Learning from the project:
• Lean approach to systematically identify
critical Xs from list of hundreds of process
parameters
• It helps to drill down to a manageable NVA’s
People involvement and Learning
Winning prize for best project in DISHAWave-V
THANK YOU“THE IMPOSSIBLE IS JUST THE POSSIBLE THAT HASN'T HAPPEN YET”
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