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”