Project Disha – Intermediate Product yield improvement

Leader: Mr. Pankaj Chaudhari Sponsor: Mr. Pravindan Gadhvi

Coordinator: Mr. Roshan Wanjari

• Kicked off in 2012 at two pilot sites, has completed four waves covering all sites

• Top driven – Steering committee chaired by MD

• Uses Lean Six Sigma approach for continuous process improvement

• A pool of over 48 Black Belts and 72 Green Belts

• Saved over INR 50 Cr since inception of the program

DISHA – Operational Excellence Program at Lupin

2

Build a sustainable operating model for improving and sustaining profitability by developing

continuous improvement capabilities within Lupin

Intermediate High Level Process Map

Stage 1 Stage 2

Stage 4

Stage 3

Stage 5 Stage 6 Stage 7

Baseline Yield of Nov-Dec 2013

4

Project Charter

Business case: Intermediate yield improvement from 0.2474

to 0.2592, which leads cost saving of 898 lac/annum against the budgeted volume of 239 MT per year.

In Scope : Steps : Stage 4,5,6 & 7 Out of Scope In-between process change shall not be considered. Solvent recovery specific Stage 4 and Stage 5 DCM are not taken into consideration.

Problem Statement: Since last 9 months Intermediate yield variation

is critical problem & variation is observed from 0.241 to 0.254

Goal Statement: Yield improvement Stage 4: From : 0.8137 to 0.819 Stage 7: From 0.3477 to 0.363. Intermediate: From 0.2474 to 0.2592. Variation (standard deviation) reduction : Intermediate: From 0.01517 to 0.00506

Team: 11 Members from Production 1 Member from Engg 1 Member from PD lab 1 Member fro PED 1 Member from QC/QA

DMAIC

Phase Jan-14 Feb-14 Mar-14 Apr-14 May-14 Jun-14

Define 12-Feb

Measure 20-Mar

Analyze 20-Apr

Improve 10-May

Control 15-Jun

Customer & Quality focus

Voice of Process

• Price reduction for the Intermediate

• Sustained quality of the Intermediate

• High variation in yield

• Gap between actual and theoretical yield

• API sales team asking for reduction in Ex factory cost.

• 20 Ton Market share can be increased in 2015-16, if cost of Production is lower. Regulatory

compliance

5

DMAIC

SIPOC

Process

Stage 1

Stage 2 In Scope

Out of Scope

Stage 3

Stage 5B

Stage 6

Stage 7

Stage 5A

Stage 4A Stage 4B Stage 4C Stage 4D Stage 4

Stage 5C

Supply Input (Qty)

Input requirement

Process Output

requirement Output (Qty)

Customer

RM suppliers

RM Specification.

of RM

Key Raw material to

Stage 7 Intermediate

Spec. of intermediate

Intermediate

Warehouse

DMAIC

Out of seven stage,

Stage no.4, 5,6 & 7 are in scope of this project &stage 4 & 5 are also

divided into sub steps.

7

Targets Validated Through 1 Sample T Test

Stage

Average yield

of April'13-Dec'13

Targeted yield is validated by 1 sample “T”

test

Stage 1 Assuming same as previous for benefit calculation.

(Out of Scope) Stage 2

Stage 3

Stage 4 0.8137 0.8190

Stage 5,6 & 7 0.3477 0.3630

Intermediate 0.2477 0.2592

Total Potential cost saving of 8.98 Cr/ Year Validated by Finance Dept.

Ho: Target is equal to Baseline Ha: Target is greater than Baseline

DMAIC

As P value is less than 0.05 accept Null hypothesis which shows that target is significant.

8

Define Phase Activity

Probability of Occurrence

Seve

rity

of

Imp

act

High Medium Low

Hig

h

Med

ium

L

ow

Risk 5

Risk 4 Risk 1

Risk 2 Risk 6

Risk 3

Risk Prioritization Grid

DMAIC

No

Risk Description

Prob.

Impact

Risk Risk Management Plan

(How to Avoid / Transfer / Mitigate / Accept)

1 Experimental and analytical support

2 3 6 Delegation of task by making responsible to concern person.

2 Input RM supplier, quality and analysis

1 3 3 Prior discussion with vendor , raising specific requirement. Avoid new vendor during project.

3 Variation in budgeted volume

1 2 2 To be done in second phase

4 Changes in process, equipment and facility

1 3 3 Risk evaluation shall be done

5 Audits (ISRS, Regulatory, vendor)

2 1 2 Rescheduling according to audit period.

6 Documentation delay

2 3 6 Escalating the issue to seniors and arranging all concern to meet and approve the same.

Risk Identification

DMAIC

• Value stream Mapping • Issue tree • Data Collection Plan • Measurement System Analysis • Process capability • Quick Wins

MEASURE

Value Stream Mapping Summary of VSM Exercise (12 Feb to 4th Mar 14 )

Step Important Insights & Quick

Wins Status

Stage 4

In process Recovery stage – Temp control up to NMT 40 C against NMT 50 C

Implemented since 15th Feb 2014,Significant improvement of 2.1% observed in Stage 4 yield.

Stage 5

Stage 5 ML Treatment - Increased caustic lye quantity from 82 lit to 98 lit per batch

Implemented Since 2nd March 2014.Significant improvement observed in yield 3.3% in IBA.

Lower temp during Stage 4 addition is favorable.

Evaluated & fixed.

Stage 6 & 7

Drying output of Stage 5 and Stage 6 to evaluate stage wise yield

Implemented on 15th March-2014. Drying done-Significant improvement observed in yield of Stage 5 (Refer insert file)

Quality of Sodium hydro sulfite on yield – As per data observations higher % LOD gives better yield

Evaluated.

DMAIC

Value stream mapping activity performed at • Shop floor (on 30 Meter chart paper) • With 18 members including PD lab

production. ( 40 hrs. activity) • Identify all hidden factors & key parameters

impacting the process

11

Issue tree

Intermediate

wt.

Reaction efficiency

Unreacted Stage 4

Unreacted Stage 4 , Unreacted Stage 5

Unreacted in Stage 5 input

Physical

Loss

Stage 4 in ANF

Stage 5 in ANF

Stage 6 and Stage 7 Intermediate in CF

Out going stream

Intermediate in Stage 6 ML

Intermediate Stage 7 ML

Stage 4 in ML/ wml

Intermediate in spent carbon

Stage 5 output in ml

Output Area

DMAIC

*ANF- Agitated Nutch Filter *ML- Mother Liquor

Significant losses were identified in the Reaction efficiency. (highlighted in red color) Loss at other areas were also identified & regularly monitored.

12

Data Collection Plan

Sub steps Performance

Measure Operational Definition

Data Source and Location How Will

Data Be

Collected

Who Will

Collect

Data

When Will

Data Be

Collected Operation Equipment

What to

measure

with unit

Stage 4

Quantity (DCM)

Monitoring of Initial level and final level, and

deriving quantity from calibration.

Charged 2014 lit.±14 lit Pre-chilled Washed

Methylene Stage 5oride in the R-3401D/R-3401F.

Before charging check the analysis.

V-3401A Quantity in

ltrs Physically/Manually

Team member

Befor /After bx charging

Time (DCM Charging)

Charging start time and end time

V-3401A Start time and

end time in min

Manually. Team

member Befor /After

DCM charging

Analysis(DCM) Withdrawal of sample for analysis from column pot

4401A/4401B V-3401A

%Methanol and % MECL2

Analysis Team

member Before bx charging

DMAIC

204 225 150 180 120 140

0

500

Stage 4 Stage 5 Stage 6 & 7

No of Parameters/ Batch No of Batches

Detailed data collection plan prepared with 580 data point in each batch. With the team of 17 members in the plant and 5 members in Analysis development Lab, 84720 data points collected.

13

Measurement System Validation

Purpose:

To validate that our Project Y or critical X’s does not have measurement system error

All our project Y is measured on HPLC ( High pressure liquid chromatography) which is highly

précised instrument with regular calibration & less manual intervention.

In few X’s were we found the manual intervention during measurement ,we performed Gage

Reproducibility & Repeatability study with two operators for measurement system validation

Sr. no Key parameter Activity Inference

1 Weighment of

Bromine at Stage 4 Gage R&R and done with two operator

GRR is 14.81% Measurement found OK

2 MEG addition Gage R&R and done with two operator GRR is 3.87%

Measurement found OK

DMAIC

Gage Repeatability & Reproducibility

The measurement systems are acceptable % GRR is < 30

The data is considered to not have potential for significant error.

DMAIC

MEG Addition by Level Indicator GRR 3.87 %

Weighment of Bromine GRR 14.81 %

Baseline Process Capability : Stage 7 Yield

Current process is not capable to meet the target specification . (Capability Analysis was carried out with target yield and with data of 150 batches)

DMAIC

Ppk -0.34

Implementation of Quick wins

• Ideas identified in the VSM is discussed & Few Quick wins were identified.

• Few ideas were also validated with the historical data wherever available .

• Those data points where historical data are not available are introduced in data collection plan.

• Quick win identified through VSM is implemented which give the lift in yield up to 40 % of targeted. ( from 0.350 to 0.356)

DMAIC

17

I-MR chart after implementation of Quick wins DMAIC

Caustic lye quantity increased in treatment of Rec DCM

VSM Ideas evaluated with data

Rotary Vacuum paddle dryer (RVPD) wise variation observed in the yield

Variation in yield observed in Thin Layer Chromatography

pass batches

DMAIC

Analyze

DMAIC

• X’s Funnel • Hypothesis testing • Regression Analysis

20

Overall process Flow

Stage 5 Stage 4 Stage 6 & 7

Process Steps

In process Ys used are : • Yield at each stage, • % product formed & • % Unreacted raw material at each stage

DMAIC

21

Stage 4 – Process Steps for Regression Analysis (Y’s chosen at each step to increase the reaction conversion)

Stage 4B Stage 4A Stage 4C Stage 4D Stage 4

Process Steps

% Stage 4B Product

Conversion

% Stage 4A Product

Conversion

% Stage 4C Product

Conversion

% Stage 4D Product

Conversion Stage 4 yield

Y variables

Y variables at each steps are showed in box below each stage. In coming slides Reducing X’s Funnel analysis method for Stage 4A demonstrated , Similar methodology used in other stages to reach critical X’s at each step. (Total 204 X’s at Stage 4 Stage – A to D sub stage)

DMAIC

22

All Possible Variables (X’s)

Critical Input Variables

• VSM • Brainstorming

• Cause and Effect Matrix

• Graphical analysis • Cp/Cpk

• Hypothesis testing • Regression

71

52

30

18 5

X’s Funnel at the end of Analyze- Stage 4A DMAIC

Similar Analysis was carried out for B to D stages also

Stage X’s from I-O

Worksheet Cause & Effect Matrix Process Capability Statistical Test

Multiple

Regression

Stage

4A

Rec DCM Qty. Rec DCM Qty. No variation in Qty.

%M/C- DCM %M/C- DCM %M/C- DCM Only 4 values of M/c

Removed by ANNOVA test

Temp Before AEN Lower CE matrix score

PTSCL %M/C NMT 2.% PTSCL %M/C NMT

2.% PTSCL %M/C NMT 2.% PTSCL %M/C NMT 2.%

PTSCL %M/C

NMT 2.%

%MeOH-DCM %MeOH-DCM Remove due to higher

CpK>4

%DCM-CHS %DCM-CHS Remove due to higher

CpK>4

Reactor A & B of -Tosyl Reactor A & B of -Tosyl Reactor A & B of -Tosyl Removed by 2 Sample T

Test

Melting Point-AEN Lower CE matrix score

NH3 addition rate NH3 addition rate NH3 addition rate NH3 addition rate NH3 addition rate

NH3 addn temp at 60min NH3 addn temp at 60

min NH3 addn temp at 60 min NH3 addn temp at 60 min NH3 addn temp-60

Final PH - at TLC-

Tosysyl

Final PH - at TLC-

Tosysyl Final PH - at TLC- Tosysyl Final PH - at TLC- Tosysyl

Final PH - at TLC-

Tosysyl

TLC observation Ok/Not

Ok

TLC observation Ok/Not

Ok

TLC observation Ok/Not

Ok 2 Sample T test TLC OK is

found significantly better.

Total

X's 71 52 30 18 5

X’s in Stage 4A is reduced by using the funnel

Finally 5 Critical parameters were identified in Stage 4 A through regression.

DMAIC

24

Cause & Effect Matrix with Plant & PD lab

X’s with scores in excess of 38 were carried forward for graphical/regression analysis

DMAIC

Sr No Stage Xs from I-O Worksheet

C&E Matrix

C & E Score Yield Quality Total

10 8

1

Stage 4A

Rec DCM Qty 4 3 64 Rec DCM Qty.

2 %M/C- DCM 5 5 90 %M/C- DCM

3 %MeOH-DCM 5 5 90 %MeOH -DCM

4 %DCM-Stage 4 5 5 90 %DCM-Stage 4

5 %IMP-DCM 5 5 90 %IMP-DCM

6 Water Qty-Stage 4 Total 7 6 118 Water Qty.- Stage 4A Total

7 Conc NH3 -Stage 4A 7 6 118 Conc .NH3 - Stage 4A

8 Reactor No-Stage 4A 5 5 90 Reactor No-Stage 4A

9 Centrifuging time 1 2 26

10 Wet Stage 3 Input 7 5 110 Wet Stage 3 Input

11 %Assay-Stage 3 8 6 128 %Assay-Stage 3

12 Melting Point-Stage 3 3 1 38

13 PTSCL

14 PTSCl Qty 7 7 126 PTSCl Qty.

15 Total PTScl 7 7 126 Total PTSCL

Process Step total Scores, Prioritized steps highlighted.

Capability analysis for Xs

Process Capability of % DCM is 2 Process Capability of dry Stage 4 1.26

Process Capability of Impurity in Cryo is 3.12 Process Capability of % M/c in DCM is 1.16

DMAIC

Hypothesis testing - PTSCL source 2-sample t-test indicates significant difference in fresh PTSCL and Rec PTSCL on Stage 4A reaction. Action: Planning to minimize the use of Rec. PTSCL in Stage 4A

DMAIC

Stage 4 Conversion

PTSCL Source

Two Sample T test of PTSCL in Stage 4A

Null Hypothesis : Conversion is same for both the sources of PTSCL Alternate Hypothesis: The conversion in fresh PTSCL is higher than recovered.

As P value is less than 0.05 we are rejecting the null hypothesis & accepting the alternate hypothesis

Annova Test for Bromine source

On the basis of this test we are preferring supplier Y for all the future requirement.

DMAIC

Null Hypothesis : % conversion is same for all the suppliers. Alternate Hypothesis % conversion is different for at least any one of the supplier.

Though the P value is 0.076 we reject the null hypothesis after discussing the case with PD lab & accept that the yield in supplier y is statically different.

Best Subset Regression

Best Subset Regression : %Product 4A

• Best Subset with higher R-Sq. Adjacent & lower Mallows Cp with minimum parameters. Regression was carried out after 2 T test and ANOVA with 18 X’s

• 5 X’s – selected – NH3 addition temp at 60 min, NH3 addition rate, impurity in stage 4A, Final PH & PTSCL M/C

DMAIC

29

List of Critical X’s prioritized at the end of Analyze

Phase of Tosylation reaction

DMAIC Critical Parameter Through Regression Final Regression Equation obtained with R-sq.

Adjacent as 64.82% i.e. 64.82 % of the variation

in % Product stage 4A is defined these 5

parameters.

Detail Unit Desired Min Max Mean

NH3 Addition Temp at 60 min. Degree C 1.5 6 1.3317

NH3 addition rate Lit/Min 4.028 7.7267 6.4699

Impurity in Stage 4A % 0 1.6 0.2742

Final Ph at Satge 4A (8.9-9.0) 8.81 9.1 8.88

PTSCL M/C % 7.59 9.2 8.8657

% product in stage 4A

30

Critical parameter at other stages are identified by implementing the similar exercise.

Sr Stage 5 1 Maximum temp Stage 4 Addition

2 Stage 4 disso. Maint. Time (min)

3 After 1st lot DMA maintaining time and quantity

4 Extra PCL-5 Qty. in Kgs 5 %IBC Rec DCM,%IMP in cryo.

Sr Stage 6 & Stage 7

1 Soda charging temp

2 Maintaining Time 30 min instead of 15 min after soda

3 pH of reaction mass after soda addition.

4 Qty. of soda in kg.

5 Sodium hydrosulphite temp at 10 min

6 Fresh water charging end temp

7 pH after hydrosulphite and maintaining

DMAIC

Sr. Stage 4A 1 NH3 addition rate

2 Final Ph at Tosyl (8.9-9.0) 3 PTSCL source

4 PTSCL M/C

5 Impurity Tosyl

Sr. Stage 4B 1 Final temp Ennamine

2 Water washing Qty-Enamine

Sr. Stage 4C 1 Final Temp-Bromine

2 R-3402 Dry dip

3 Stirring time 30 after morpholine

4 Bromine supplier

Sr. Stage 4D 1 PH-cyclize

2 Total Cyclize maintaining time

3 Imp Cyclize

4 Unreacted Ennamine-Bromo stage

5 End Temp of Maintaining

Sr. Stage 4

1 Final temperature during recovery-Max

2 Qty . of Rec DCM +Methanol

3 Stage 4 Dryer RVPD (Higher temp)

Critical Parameter After Regression

IMPROVE

DMAIC

• Brainstorming • DOE • FMEA

Stage 4 stage Critical X’s under control

32

Stage Detail Unit Before After

Remarks Mean

Std. dev .

Mean Std. dev.

Stage 4A Avg. NH3 rate Lit/mi

n 6.5 0.7 5.5 0.24

Orifice applied (5mm and 6mm respectively) to control NH3 addition rate, cleaning frequency 10 days.

Stage 4A Final PH - at TLC- Tosyl

7.86 0.19 7.89 0.08 Presently Manually controlled, future plan of application of on line ph meter with addition pump.

Stage 4C

Morpholine addition

stirring time Min 31.7 14.6 40 -

Morpholine stirring time maintained 40 min instead of 25 min

Bromine addition time

min 8.85 2.14 - - Charging time should not increase above 7-8 min. Possibility to work out for fast addition of bromine in future.

In this data we can see that the mean is shifted & variation is also reduced

DMAIC

Stage 6 : Critical X’s under control

33

Detail Unit Before After

Remarks Mean Std. dev. Mean Std. dev.

Soda charging temp 0C 43 2.7 48 0.87 Presently charging started at 45°C ,by applying hot water if required

pH of reaction mass after soda addition

5.22 0.09 5.22 0.1 ph is maintained NLT 5.0

Maintaining Time after soda

Min 10.2 6.7 30 Maintaining time of 30 min started

Qty. of soda in kg Kg 55.2 2.1 55.6 1.3 Qty. of soda charged is NLT35 KG

Sodium hydrosulphite temp at 10 min

0C 30.8 1.8 34.3 1.12 Sodium hydrosulphite charging started at 40°C and 150 kg sodium hydrosulphite charged within 10min

Fresh water charging end temp

0C 33.7 2.2 30.7 1.05 Fresh water charging started after bringing temp of mass up to 48°C

ph after Hydrosulphite and maintaining

- 4.53 0.16 4.71 0.08 ph is maintained NMT 4.8

DMAIC

In all the critical X’s mean were shifted & standard deviation reduced. And to maintain the parameters within the desired limit auto system like online PH

meter & peristaltic pump were installed in few areas.

7 Critical parameters were identified in Stage 6, where the Theoretical yield is lowest out of all the stages.

DOE to be planned to further optimize the critical parameters to get the maximum yield with complete control.

Out of Seven, 3 parameters i.e. PH of reaction mass after soda, sodium hydrosulphite temp at 10 min & PH after hydrosulphite & maintaining is not under direct control.

Screening DOE done with 4 parameters & 2 Leveled at pilot plant.

On the basis of screening DOE , Optimization DOE planned with 2 factors & 2 Level Full factorial DOE with 2 replicates & 1center point.

Stage 6 : DOE Planning

Experiment performed in Pilot lab as per the Run order.

DMAIC

DOE on Stage 6 parameters

Implementation of DOE learnings leads to major improvement in the yield.

DMAIC

In Intermediate after implementation of the

critical parameter identified through

regression further scope observed for which Full factorial DOE planned

with 2 Factors at 2 Levels including center point.

0.3677 yield can be obtained by optimizing this two parameters

CONTROL

DMAIC

• Control Limit • Control Plan for Sustenance • Before/After Process Capability

37

Control limits

Control Action Responsible Individual

Lower Control Limit

Target Value Upper

Control Limit

Current

Avg. NH3 rate in stage 4A

Operating officers

4.9 5.5 6.1 5.5

Final PH - at TLC- Stage 4A 7.68 7.87 8.06 7.87

Stage 4B final temperature 19.57 20.36 21.15 20.36

Final temp Stage 4B 20 20.6 27.2 20.6

Final Temp-Bromine -9.7 -6.85 -4.2 -6.85

Bromine supplier

PH- Stage 4D 0.53 0.68 0.84 0.68

Total Stage 4D maintaining 180 180 540 188

End Temp of Maintaining 35.4 40.85 45 40.85

Final temperature during recovery-Max 36 42.8 49 43

Stage 4 disso. Maint. Time (min)

Operating officers

10 15 30 12.84

After 1st lot DMA maintaining time 15 30 400 53.41

Maximum temp Stage 4 ADDTN -15 -12 -8.2 -11.03

%IBC Rec DCM 0 0.06 0.5 0.06

%IMP in Cryo. 0.06 0.4 0.84 0.354

DMAIC

Control limits established for all critical parameters & tracking through Dashboard in Plant

38

Process Control Plan Monitoring

Step Actions Frequency Responsibility

Stage 4 1. Cleaning of Orifice at Dil. Ammonia addition

Stage 4 A 10 Days

Section in charge/Executive

Stage 4 Water washing at Stage 4B :-Water meter

calibration to be done and if any error replace it with new one.

Weekly Section in

charge/Executive

Stage 4 End Temp Of Maintaining :- Orifice at Stage 4

maint. Reactor to be cleaned.

15 days Section incharge/Executive

Stage 4 Recovery Time & Temp :-Vacuum drop checking of

Stage 4 recovery system 15 days

Section in charge/Executive

Stage 4 RVPD Vacuum & temp :- Vacuum line filter

cleaning. 15 days Section incharge/Executive

Stage 5 Stage 5 ANF bag replacement Plant incharge

Stage 6 HCL charging time at Stage 6 :-Cleaning of Orifice in

HCL line 15 days Section incharge/Executive

Stage 6 Stage 6 Methanol quality :- Re distillation After 40 Batch Plant incharge

Stage 7 HCL charging time at Stage 7 :-Cleaning of Orifice in

HCL line 15 days

Section in charge/Executive

DMAIC

39

Yield after Implementation

Overall yield Stage 4 Stage 5, 6 & 7

Baseline 0.2474 0.8137 0.3477

Target 0.2592 0.8193 0.3630

July 0.264 0.8298 0.3687

0.2474

0.8137

0.3477 0.2592

0.8193

0.3630 0.264

0.8298

0.3687

0

0.4

0.8

1.2

DMAIC

40

Before & After Process capability DMAIC

For the specific customer requirement we are using IBA / MEG solvent for isolation of product in Stage 5. In IBA stage with the implementation of solution theme yield improvement of 0.363 & above

obtained , at the same time similar improvement was not observed in the MEG batches. Due to which the yield after improvement is also observed below 0.363 which impact the

Process capability

People involvement: At all stages of project and primarily for the following activities

1. Creation of VSM

2. Data collection

3. Brainstorming

4. DOE & Pilots

5. Sustenance.

• Learning from the project:

• This is statistical data base approach where critical X’s responsible for output is identified in systematic way started with hundreds of X’s and further drill down to manageable level by using different LSS tools to get maximum benefit with minimum efforts.

• Team understood the power of DMAIC. This was an eye opener in a product where yield was almost stable for last 5 years

41

People involvement and Learning

Project leader & Team appreciated by Plant head

DMAIC

Innovative Methodology

Quantification of impact of multiple X’s on Y

Statistically determine the relationship of Y = f(X1, X2, X3…..)

Interaction effect of multiple parameters in multi-stage and complex process.

Challenging the “Status quo”.

In Wave 4 we got financial saving of 9 Cr validated by our finance team & in Wave

5 We are again taking a stretch target of 10 Cr potential saving. ( 5% improvement

in the yield)

Similar Methdology adopted for improvement in yield, solvent, Engineering and also in

Administration & HR departments.

DMAIC

Way Ahead

43

Thank You Never doubt that a small group of thoughtful committed

people can change the world:

Indeed it’s the only thing that ever has !

Disha Team- Lupin, Ankleshwar Yes I Can...Yes I Can... Yes We Can...Yes LUPIN Can.