SPC in Pharmaceutical Industry One Day 93-01-26 PDF

StatisticalProcessControl,SPC
in Pharmaceutical Industry
inPharmaceuticalIndustry

OperationsManagement

Amir Mehdizadeh, Ph.D.
AmirMehdizadeh,Ph.D.
a_mehdizadeh@yahoo.com
www.ofoghpharmed.com
April 15, 2014
Statistical Process Control, SPC

Dr. Mehdizadeh

L
LearningObjectives
i Obj ti
SPC

.
Causesofvariation
7 SPC
Controlcharts
xbar,R,p,andccharts
IshikawaDiagram Causeandeffectdiagrams
Processcapability Processcapabilityindex
Concept sixsigma
Conceptsix
sigma
2

Dr. Mehdizadeh
April 15, 2014
SPC

-1

-2
Processcapabilityindex
-3 Process
capabilityindex

Tappeddensity
Tapped density

-4

-5
Processcapabilityindex
-6 CpK
3

Dr. Mehdizadeh
April 15, 2014
SPC

PQR
QRM

cGMPFDA
PIC/S
/


Dr. Mehdizadeh
April 15, 2014
cGMPFDA
(b)Validinprocessspecificationsforsuchcharacteristicsshallbeconsistent
(b)
Valid in process specifications for such characteristics shall be consistent
withdrugproductfinalspecificationsandshallbederivedfromprevious
acceptableprocessaverage andprocessvariabilityestimates wherepossible
anddeterminedbytheapplicationofsuitablestatisticalprocedures
dd
db h
l
f
bl
l
d
where
h
appropriate.Examinationandtestingofsamplesshallassurethatthedrug
productandinprocessmaterialconformtospecifications.
April 15, 2014

Dr. Mehdizadeh
AnIntroductiontoSPCandSixSigma
g
Wedontknowwhatwedontknow.

Wecantactonwhatwedontknow.

Wewontknowuntilwesearch.

We wonttsearchforwhatwedon
Wewon
search for what we donttquestion.
question.

Wedontquestionwhatwedontmeasure.

Hence,wejustdontknow.
Dr Mikel Harry
Dr.Mikel
April 15, 2014

Dr. Mehdizadeh

THE BIGGEST ISSUE
THEBIGGESTISSUE


Dr. Mehdizadeh
April 15, 2014

'lean manufacturing' methods
'leanmanufacturing'methods
AstraZenecawasoneofthefirstpharmaceuticalcompaniesintheworld
f h f
h
l
h
ld
toadoptToyota's 'leanmanufacturing'methods.
in Pharmatechnologist.comvisitedthefirm
com visited the firm'ssplantinSdertlje
plant in Sdertlje tofind
to find
inPharmatechnologist
outwhatimpactthiswayofworkingishavingonproductivity
6Sigma
improvements
Lean
improvements
April 15, 2014

Dr. Mehdizadeh
2013 10
Top 10 Best Pharmaceutical Companies In 2013
Top10BestPharmaceuticalCompaniesIn2013
1.Johnson&Johnson
h
h
UnitedStates
d
2.Pfizer UnitedStates
3.Roche
h Switzerland
i
l d
4.GlaxoSmithKline UnitedKingdom
5.Novartis
i Switzerland
S i
l d
6.Sanofi France
7.AstraZeneca
7 A
Z
U i d Ki d
UnitedKingdom
8.AbbottLaboratories UnitedStates
9.Merck&Co
9 M k & C UnitedStates
U i dS
10.BayerHealthCare Germany
April 15, 2014

Dr. Mehdizadeh
Lean Six Sigma Timeline

LeanSixSigmaTimeline
Guinness
Brewery
1900
Ford
Assembly
Line
Line
April 15, 2014
Shewhart
Introduces
SPC
1930
Gilbreth,Inc.
Management
Theory
Industrial
Engineering
Dr. Mehdizadeh
Deming
D
i
14Points
7DeadlyDiseases
1950
ToyotaProduction
System
10

StatisticalQualityControl,SQC
Q
y
, Q
StatisticalProcessControl,SPC
1930

SPC,StatisticalProcessControl,isaprocessthatwasdesigned inthe
1930stocharacterizechangesandvariation inprocessfromastandard.
SPC
.

Itcanbeusedforboth
attributes and
variables
April 15, 2014

Dr. Mehdizadeh
11

S
SourcesofVariation
f V i ti

Variation existsinallprocesses.

Variation canbecategorizedaseither:

Natural,CommonorRandomcauses ofvariation,or
Randomcausesthatwecannotidentify
Unavoidable,e.g.slightdifferencesinprocessvariableslike
Unavoidable e g slight differences in process variables like
voltage,qualityofmachine,servicetime,temperature

SpecialorAssignablecauses ofvariation
Causescanbeidentifiedandeliminated:pooremployeetraining,
,
g p
worntool,machineneedingrepair
April 15, 2014

Dr. Mehdizadeh
12

Understanding Variability
UnderstandingVariability
Variationexistsineverything.Eventhebestmachine
cannotmakeeveryunitexactlythesame.
Improvedcapability,becomesanecessity,duetothe
needof:
improveddesigns
lowercosts
betterperformance
Allofthisleadstotheneedoftightertolerances
g
Thismeansthattheabilitytooperatetoatighttolerance,without
p
producingdefectsbecomesamajoradvantage
g
j
g
April 15, 2014

Dr. Mehdizadeh
13

D
DescriptiveStatistics
i ti St ti ti
DescriptiveStatisticsinclude:
l d
n

TheMean
h
measureofcentraltendency
f
l
d
x=
TheRange differencebetween
largest/smallest observations in a set of data
largest/smallestobservationsinasetofdata
x
i =1

StandardDeviationmeasurestheamountof
Deviation measures the amount of
Standard
datadispersionaroundmean
DistributionofDatashape
Normalorbellshapedor
Skewed
April 15, 2014
(x
n

Dr. Mehdizadeh
i=1
n 1
14
Descriptivestatistics

Inferentialstatistics

15

Dr. Mehdizadeh
April 15, 2014
Descriptivestatisticssummarizethepopulationdatabydescribingwhatwas
observedinthesamplenumericallyorgraphically.Numericaldescriptors
includemean andstandarddeviation forcontinuousdata types(likeheights
orweights),whilefrequencyandpercentagearemoreusefulintermsof
describingcategoricaldata (likerace).

Inferentialstatistics usespatternsinthesampledatatodrawinferences
aboutthepopulationrepresented,accountingforrandomness.These
inferencesmaytaketheformof:answeringyes/noquestionsaboutthe
data (hypothesis testing), estimating numerical characteristics of the data
data(hypothesistesting),estimatingnumericalcharacteristicsofthedata
(estimation).Inferencecanextendtoforecasting,prediction andestimation
ofunobservedvalueseitherinorassociatedwiththepopulationbeing
studied; it can include extrapolation andinterpolation.
studied;itcanincludeextrapolation
and interpolation
April 15, 2014

Dr. Mehdizadeh
16

Di t ib ti
DistributionofData
fD t
Normaldistributions
ld
b
April 15, 2014
Skeweddistribution

Dr. Mehdizadeh
17

Normal Distribution
NormalDistribution
April 15, 2014

Dr. Mehdizadeh
18
April 15, 2014

Dr. Mehdizadeh
19
AUC=0.135%
AUC=0.135%
April 15, 2014

Dr. Mehdizadeh
20

Understanding Variability
UnderstandingVariability
Variability isinherentineveryprocess,aswellaspharmaceuticalprocesses
:
Natural orcommoncauses,e.g.LODvariationingranulation
:
Specialorassignablecauses,e.g.mistakeintimeandtemperature
settingindryingstep.
SPC

Providesastatisticalsignal
id
i i l i
l whenassignablecauses
h
i
bl
arepresent
Detectandeliminateassignablecausesofvariation
April 15, 2014

Dr. Mehdizadeh
21

Natural Variations
NaturalVariations

Naturalvariations intheinherent ofproductionprocess

Thesearetobeexpected
) (
Outputmeasuresfollowanormaldistribution
Output measures follow a normal distribution (bellshape)
(bell shape)
.
Foranydistributionthereisameasureofcentraltendencyanddispersion
April 15, 2014

Dr. Mehdizadeh
22

Assignable Variations
AssignableVariations

.
Variationsthatcanbetracedtoaspecificreason (machinewear,
misadjusted equipment fatigued or untrained workers)
misadjustedequipment,fatiguedoruntrainedworkers)
SPC
TheobjectiveofSPC istodiscover whenassignablecausesarepresent and
eliminatethem
April 15, 2014

Dr. Mehdizadeh
23

Samples

(a) Samplesoftheproduct,sayfiveboxes
of cereal taken off the filling machine
ofcerealtakenoffthefillingmachine
line,vary fromeachotherinweight
F
Frequency
y
Tomeasuretheprocess,wetakesamplesandanalyzethesample
statistics followingthesesteps
Eachofthese
representsone
(
)

-1
sampleoffiveboxes
l f fi b
ofcereal

# #
# # #
# # # #
# # # # # # #
#
# # # # # # # # #
Weight
g
April 15, 2014

Dr. Mehdizadeh
24

Samples
-2
Thesolidline
represents the
representsthe
distribution
(b) Afterenoughsamplesare
takenfromastableprocess,
Frequency
theyformapatterncalleda
distribution
April 15, 2014
Weight

Dr. Mehdizadeh
25

Samples
( ) -3

(c) Therearemanytypesofdistributions,includingthenormal(bell
shaped)distribution,butdistributionsdodifferintermsofcentral
Frequency
tendency(mean),standarddeviationorvariance,andshape
Centraltendency
Weight
April 15, 2014
Variation
Weight
Shape
Weight

Dr. Mehdizadeh
26

Samples
-4

(d) Ifonlynaturalcauses of
variation arepresent,the
are present the
outputofaprocess formsa
Frequenccy

Prediction
Weight
distribution thatisstableover
that is stable over
timeandispredictable
April 15, 2014

Dr. Mehdizadeh
27

Samples
BatchReconciliation
-5
Range
Yield

PQR
(e) Ifassignablecauses are
?
?? ??
?
?
?
?
?
?
?
?
?
??
??
?
present,theprocessoutput
isnotstableovertimeandis
Fre
equency
Prediction
notpredicable
Weight
28

Dr. Mehdizadeh
April 15, 2014
Statistical Analysis in Pharmaceutical

Processes
April 15, 2014

Dr. Mehdizadeh
29
-1
1.
FishboneDiagrams
2.
Histograms
3.
ParetoAnalysis
4.
Flowcharts
5
5.
Scatter Plots
ScatterPlots
6.
RunCharts
7.
ControlCharts
April 15, 2014
-2
-3
-4
-5
-6
-7

Dr. Mehdizadeh
30
Dr.WalterShewhart
Dr
Walter Shewhart
ControlCharts
April 15, 2014

Dr. Mehdizadeh
31

Types of Data
TypesofData
Variables

Attributes

Defectrelatedcharacteristics
Characteristicsthatcantakeany
real value
realvalue

Maybeinwhole
May
be in whole orinfractional
or in fractional
numbers

Classifyproductsaseithergood
products as either good
Classify
orbad orcountdefects
Continuousrandomvariables

Categorical&discreterandomvariables
Categorical & discrete random variables
April 15, 2014

Dr. Mehdizadeh
32

Q lit
Quality
Quality
l meansfitnessforuse
f
f
qualityofdesign
qualityofconformance
li
f
f
Quality isinverselyproportionaltovariability.
Manufacturingbaseddefinition:Conformancetospecifications
f
i b d d fi i i
C f
ifi i
Theproducthasbothvariablespecifications (measurable)and
attributable specifications (non
attributablespecifications
(nonmeasurable)
measurable)thatmanufacturing
that manufacturing
monitorsandensuresconformance
Productbaseddefinition:quantitiesofproductattributes
Attributesarenonmeasurabletypesofdata
Whatareallthedifferentfeatures
April 15, 2014

Dr. Mehdizadeh
33

Control Charts
ControlCharts
.

Constructedfromhistoricaldata,thepurposeofcontrolchartsistohelp
distinguishbetween naturalvariations andvariationsduetoassignable
causes
8 4

. 12kp
Hardnessspecification:48kp
April 15, 2014

Dr. Mehdizadeh
34
1
2
3
4
5
6
7
8
9
10
Mean
SD or
Batch 1
200
201
202
198
195
207
204
196
206
203
201.2
4.02
April 15, 2014
Batch 2
199
201
202
198
200
198
203
197
199
198
199.5
1.95
Batch 3
202
201
200
199
201
199
200
198
201
200
200.1
1.19
210
208
206
204
202
Batch1
200
Batch2
198
Batch3
196
9
194
192
190
0

Dr. Mehdizadeh
10
12
35
-SPC
SPC M th d D l i C t l Ch t
SPCMethodsDevelopingControlCharts

(

. LCL UCL CL
ControlCharts(QCcharts)showsampledataplottedonagraphwith
Charts (QC charts) show sample data plotted on a graph with
Control
CL,UCL,andLCL.

.
Controlchartforvariables areusedtomonitorcharacteristicsthatcanbe
measured e g hardness weight dissolution yields and friability
measured,e.g.hardness,weight,dissolution,yields,andfriability.

Control
Controlchartsforattributes
charts for attributes areusedtomonitorcharacteristicsthathave
are used to monitor characteristics that have
discretevalues andcanbecounted,e.g.%defectiveinbottlingand
capping,or#ofbadorimperfectinblistering,etc.
April 15, 2014

Dr. Mehdizadeh
36

S tti Control
Setting
C t l Limits
Li it
Percentageofvaluesundernormal
f l
d
l
curve
April 15, 2014
Controllimitsbalanceriskslike
TypeIerror

Dr. Mehdizadeh
37

C t l Ch t f V i bl
ControlChartsforVariables
R X
Usexbar andRbar chartstogether

Usedtomonitordifferentvariables
R X
Xbar &Rbar Chartsrevealdifferent

problems

.
Isstatisticalcontrolononechart,outof
controlontheotherchart?OK?
April 15, 2014

Dr. Mehdizadeh
38

C t l Ch t f V i bl
ControlChartsforVariables
( ) X
Usexbar chartstomonitorthechangesinthemeanofaprocess (central
tendencies)
. R
UseRbar chartstomonitorthedispersionorvariability oftheprocess

Systemcanshowacceptablecentraltendenciesbutunacceptablevariability,or
.

Systemcanshowacceptablevariabilitybutunacceptablecentraltendencies
April 15, 2014

Dr. Mehdizadeh
39

Constructing an X bar Chart:
ConstructinganXbarChart:
Aqualitycontrolinspectoratthesoftdrinkcompanyhastakenthreesamples
withfourobservationseachofthevolumeofbottlesfilled.Ifthestandard
deviationofthebottlingoperationis0.2ounces,usethebelowdatatodevelop
control charts with limits of 3 standard deviations for 16 oz bottling operation
controlchartswithlimitsof3standarddeviationsfor16oz.bottlingoperation.
Time1
Time2
Time3
Observation1
15.8
16.1
16.0
Observation2
16.0
16.0
15.9
Observation3
15.8
15.8
15.9
Observation4
15.9
15.9
15.8
where ( k )is the # of sample means and (n)

is the # of observatio ns ineach sample
15.875
15.975
15.9
UCL x = x + z x
0.2
0.3
0.2
LCL x = x z x
Samplemeans(Xbar)
Sampleranges(R)
April 15, 2014
Center line and control limit

formulas
x 1 + x 2 + ... x n
x=
, =
x
k
n

Dr. Mehdizadeh
40

Solution and Control Chart (x bar)
SolutionandControlChart(xbar)
Time 1
Time1
Time 2
Time2
Time 3
Time3
Observation1
15.8
16.1
16.0
Observation2
16.0
16.0
15.9
Observation3
15.8
15.8
15.9
Observation4
15.9
15.9
15.8
15 875
15.875
15 975
15.975
15 9
15.9
0.2
0.3
0.2
Centerline(xdoublebar):
l
( d bl b )
15 875 + 15.975
15.875
15 975 + 15.9
15 9
x=
= 15.92
3
Sample means (Xbar)

Samplemeans(X
bar)
Controllimitsfor 3 limits:
Sampleranges(R)
0.2
= 16.22
UCL x = x + z x = 15.92 + 3
4
0.2
= 15.62
LCL x = x z x = 15.92 3
4
April 15, 2014

Dr. Mehdizadeh
41

X B C t l Ch t
XBarControlChart
April 15, 2014

Dr. Mehdizadeh
42

Setting Chart Limits
SettingChartLimits
ForxChartswhenweknow
Upper control limit (UCL) = x + zx

Lower control limit ((LCL)) = x - zx
where
April 15, 2014
x = mean of the sample means or a target value set for

the process
p
z = number of normal standard deviations
x = standard deviation of the sample means = / n
= population
l ti
standard
t d d deviation
d i ti
n = sample size

Dr. Mehdizadeh
43

C t l Ch t f R
ControlChartforRange(R)
(R)
Factorsforthreesigmacontrollimits
Factors for three sigma control limits
Center Line and Control Limit
formulas:
R=
0.2 + 0.3 + 0.2

= 0.233
233
3
UCLR = D4R = 2.28(0.233) = 0.53

LCLR = D3R = 0.0(0.233) = 0.0
April 15, 2014
Sample Size
(n)
Factor for x-Chart
2
3
4
5
6
7
8
9
10
11
12
13
14
15

Dr. Mehdizadeh
A2
1.88
88
1.02
0.73
0.58
0.48
0.42
0.37
0 34
0.34
0.31
0.29
0 27
0.27
0.25
0.24
0.22
Factors for R-Chart
D3
0.00
0
00
0.00
0.00
0.00
0.00
0.08
0.14
0 18
0.18
0.22
0.26
0 28
0.28
0.31
0.33
0.35
D4
3.27
3
2.57
2.28
2.11
2.00
1.92
1.86
1 82
1.82
1.78
1.74
1 72
1.72
1.69
1.67
1.65
44
R
R B C t l Ch t
RBarControlChart
April 15, 2014

Dr. Mehdizadeh
45
A2 Rbar
S
SecondMethodfortheXbarChartUsingRbarandtheA2Factor
d M h d f h X b Ch U i R b
d h A2 F

Usethismethodwhensigma fortheprocessdistributionisnotknow

Controllimitssolution:
R=
0.2 + 0.3 + 0.2

= 0.233
3
UCL x = x + A 2 R = 15.92
15 92 + (0.73
0 73)(0.233)
(0 233) = 16.09
16 09
LCL x = x A 2 R = 15.92 (0.73)(0.233) = 15.75
April 15, 2014

Dr. Mehdizadeh
46

C t l Ch t f Att ib t P Ch t & C Ch t
ControlChartsforAttributes:PCharts&CCharts
/
/ :
(
)
Attributesarediscreteevents:yes/noorpass/fail
P

UsePCharts forqualitycharacteristics thatarediscrete andinvolve
yes/noorgood/bad decisions
Numberofleakingtubesinaboxof48
Numberofbrokeneggsinacarton
C
UseCCharts fordiscretedefectswhentherecanbemorethanone
defect per unit
defectperunit
Numberofdefectssuchindistinctiveengraving(batchNo.)andbadblisters
Numberofcomplaintspercustomeratahotel
Number of complaints per customer at a hotel
April 15, 2014

Dr. Mehdizadeh
47
PChartExample: Aproductionmanagerforatirecompany hasinspectedthenumberof

defectivetiresinfiverandomsampleswith20tiresineachsample.
The table below shows the number of defective tires in each sample of 20 tires
Thetablebelowshowsthenumberofdefectivetiresineachsampleof20tires.
Calculatethecontrollimits.
Sample
Number
of
D f i
Defective
Tires
Number of
Tires in each
S
Sample
l
Proportion
Defective
20
0.15
20
0.10
20
0.05
20
0.10
20
0.05
T
Total
l
100
0 09
0.09
April 15, 2014
Solution:
CL = p =
p =
# Defectives
9
=
= 0.09
TotalInspected 100
p(1 p )
=
n
(0.09)(0.91)
= 0.064
20
UCLp = p + z ( ) = 0.09 + 3(0.064) = 0.282

LCLp = p z ( ) = 0.09 3(0.064)
(
) = 0.102 = 0

Dr. Mehdizadeh
48
P
P ControlChart
P
C t l Ch t
April 15, 2014

Dr. Mehdizadeh
49
CChartExample:Thenumberofweeklycustomercomplaintsare
monitoredinalargehotelusingacchart.
Develop threesigmacontrollimitsusingthedatatablebelow.
Week
1
2
3
4
5
6
7
8
9
10
Total
NumberofComplaints
Number
of Complaints
3
2
3
1
3
3
2
1
3
1
22
April 15, 2014
S l ti
Solution:
C =C=
CL
# complaints 22
=
= 2.2
22
# of samples 10
UCLc = c + z c = 2.2
2 2 + 3 2.2
2 2 = 6.65
6 65
LCLc = c z c = 2.2 3 2.2 = 2.25 = 0

Dr. Mehdizadeh
50
C
C ControlChart
C
C t l Ch t
April 15, 2014

Dr. Mehdizadeh
51
StatisticalProcessControl
ParetoDiagrams
April 15, 2014

Dr. Mehdizadeh
52

Pareto Diagrams
ParetoDiagrams
Vilfredo Pareto
%20 %80 : Italyswealth
80%heldby20%ofpeople;Usedwhenanalyzingattributes
.

Thissamedistributionhasbeenobservedinotherareasandhasbeen
termedtheParetoEffect.
%80 :
.
%20
TheParetoeffect evenoperatesinqualityimprovement:80%of
problemsusuallystemfrom20%ofthecauses.
Dr. Mehdizadeh
53

Pareto Diagrams
ParetoDiagrams

Paretocharts areusedtodisplaytheParetoprinciple inaction,

.
arrangingdatasothatthefewvitalfactors thatarecausingmostofthe
problemsrevealthemselves.

.
Concentrating improvementeffortsonthesefewwillhaveagreater
impactandbemorecosteffective thanundirectedefforts.
April 15, 2014

Dr. Mehdizadeh
54

Pareto Diagrams
ParetoDiagrams

WhatisaParetoChartusedfor?

Todisplay therelativeimportanceofdata

Todirect effortstothebiggestimprovementopportunity by
highlighting thevitalfew.
April 15, 2014

Dr. Mehdizadeh
55

C t ti
ConstructingaParetoChart
P t Ch t

.
Determinethecategories andtheunitsforcomparisonofthedata,such
asnumberorfrequencyyield,weightvariation,cost,ortime.

Total the raw data ineachcategory,thendeterminethegrandtotalby
in each category, then determine the grand total by
Totaltherawdata
addingthetotalsofeachcategory.
.
Reorderthecategories
R
d th
t
i fromlargesttosmallest.
f
l
tt
ll t
)
.(100
Determinethecumulativepercent ofeachcategory(i.e.,thesumof
eachcategoryplusallcategoriesthatprecedeitintherankorder,
dividedbythegrandtotalandmultipliedby100).
April 15, 2014

Dr. Mehdizadeh
56

C t ti
P t Ch t

Drawandlabelthelefthandverticalaxis withtheunitofcomparison,such
asfrequency,costortime.
.
Drawandlabelthehorizontalaxiswiththecategories.Listfromlefttoright
i
inrankorder.
k d
.
.

Drawandlabeltherighthandverticalaxis from0to100percent.The100
percentshouldlineupwiththegrandtotalonthelefthandverticalaxis.

Beginningwiththelargestcategory,drawinbarsforeachcategory
representingthetotalforthatcategory.
ep ese t g t e tota o t at catego y
April 15, 2014

Dr. Mehdizadeh
57

C t ti
P t Ch t

Drawalinegraph beginningattherighthandcornerofthefirstbar to
representthecumulativepercentforeachcategoryasmeasuredonthe
right hand axis
righthandaxis.
.
Analyzethechart.
. %80 %20
Usuallythetop20%ofthecategorieswillcompriseroughly80%ofthe
cumulativetotal.
April 15, 2014

Dr. Mehdizadeh
58

Constructing a Pareto Chart

Letsassumewearelistingalltherejectedproductsthatareremoved
fromacandymanufacturinglineinoneweek

Firstweputtherejectsinspecificcategories
Nowrapper .
Nocenter .
Wrongshape .
Shortcut .
W
Wrapperopen

.
Underweight .
Overweight .
April 15, 2014

Dr. Mehdizadeh
59


Thenwetallyhowmanyofeachcategorywehave
1.
Nowrapper 10
2.
Nocenter 37
3
3.
Wrongshape
h
53
3
4.
Shortcut 6
5. Wrapperopen 132
6.
Underweight 4
7.
Overweight 17
Getthetotalrejects 259
April 15, 2014

Dr. Mehdizadeh
60


Developapercentageforeachcategory
1.
Nowrapper 10/259=3.9%
/
2.
Nocenter 37/259=14.3%
3
3.
Wrongshape
h
53/259=20.5%
3/2 9 20 %
4.
Shortshot 6/259=2.3%
5
5.
W
Wrapperopen
132/259=51%
132/259 51%
6.
Underweight 4/259=1.5%
7
7.
O
Overweight
i h 17/259=6.6%
17/259 6 6%
April 15, 2014

Dr. Mehdizadeh
61

Now place the counts in a histogram largest to smallest
Nowplacethecountsinahistogram,largesttosmallest
100
90
80
70
60
51%
50
40
30
20.5%
14.3%
20
10
0
April 15, 2014
Wrapper
Open
No Center
6.6%
3 9%
3.9%
No Wrapper

Dr. Mehdizadeh
2.3%
1.5%
Underweight
62

Finally add up each and plot as a line diagram
Finally,addupeachandplotasalinediagram
100
92 4%
92.4%
90
98 6%
98.6%
100 1%
100.1%
85.8%
80
C
Cumulativepercentageline
l ti
t
li
71.5%
70
60
96 3%
96.3%
51%
50
40
30
20.5%
14 3%
14.3%
20
10
0
Wrapper
Open
April 15, 2014
No Center
6.6%
3.9%
2.3%
No Wrapper

Dr. Mehdizadeh
1.5%
Underweight
63

Cumulative percentage line
Cumulativepercentageline
100
92.4%
90
98.6%
100.1%
2.3%
1.5%
85.8%
80
71 5%
71.5%
70
60
96.3%
51%
50
40
30
20.5%
20
14.3%
6 6%
6.6%
10
0
April 15, 2014
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Open
No Center
3.9%
No Wrapper

Dr. Mehdizadeh
Underweight
64
ProcessCapability,Cp
Process
Capability Cp
ProcessCapabilityIndex(Ratio),CpKorCpk
April 15, 2014

Dr. Mehdizadeh
65

Process Capability
ProcessCapability

.

)

SOP

.
:

-1 X 3S
-2 Cp
-3 NormalDistribution
66

Dr. Mehdizadeh
April 15, 2014
X 3S

-1 Targetvalue 200
-2 USP 190
210 .
.
200

-3
-4 SD
IPQC

.

-5 SOP
.
-6 SD 2
194 206 )
( .
67

Dr. Mehdizadeh
April 15, 2014

Cp- Process
P
C
Capability
bilit Index
I d

U
Upper
S tan dard
d d Limit
Li i Lower
L
S tan dard
d d lim
li it
i
Cp =
6
USL LSL
CP =
6

C PK
April 15, 2014
USL X X LSL
= Minimum
,
3
3

Dr. Mehdizadeh
68
April 15, 2014

Dr. Mehdizadeh
69
April 15, 2014

Dr. Mehdizadeh
70

Cp ProcessCapabilityIndex
Process Capability Index
Design
Specifications
(a) Natural variation
exceeds design
specifications;
process is not capable of
meeting specifications all
tthe
e ttime.
e
Process
Design
Specifications
(b) Design specifications and

natural variation the same;
process is capable of
meeting specifications most
of the time.
Process
April 15, 2014

Dr. Mehdizadeh
71

Cp ProcessCapabilityIndex
Process Capability Index
Design
Specifications
(c) Design
specifications greater
than natural variation;
process is capable of
always conforming to
specifications.
p
P
Process
Design
Specifications
(d) Specifications greater

than natural variation, but
process off center;
capable but some output
will not meet upper
specification.
April 15, 2014

Dr. Mehdizadeh
Process
72
Processcapabilityistheabilityoftheprocesstomeetthe
desired quality (as measured by the specifications)
desiredquality(asmeasuredbythespecifications)
Natual Tolerance Limits
LNTL
-6
-5
-4
-3
UNTL
-2
-1
Standard Deviations
April 15, 2014

Dr. Mehdizadeh
73
Processcapabilityistheabilityoftheprocesstomeetthe
desired quality (as measured by the specifications)
desiredquality(asmeasuredbythespecifications)
Various Cp Values In Relationship

to Specifications
LSL
USL
Cp = 2.00
Cp = 1.33
Cp = 1.00
Cp = 0.75
April 15, 2014

Dr. Mehdizadeh
74
Cpk ) (
EffectsofReducingVariabilityonProcessCapability
Nominal value
Six sigma
Four sigma
Two sigma
Lower
specification
Upper
specification
Mean
April 15, 2014

Dr. Mehdizadeh
75
One Sigma Shift

LSL
USL
Cp = 1.33
-6
-5
-4
-3
-2
-1
Standard Deviations
April 15, 2014

Dr. Mehdizadeh
76
How to Calculate CP and CPK

HowtoCalculateCPandCPK
Step1
Calculatethesamplemean(xbar) thesumtotalofindividual
variables divided by the total number of variables
variablesdividedbythetotalnumberofvariables.
Step2
Determinethestandarddeviationofthesamples.Itisdenotedby
the standard deviation of the samples It is denoted by
Determine
Greeklettersigma.
Step3
Defineandkeepfixedupperspecificationlimit(USL)andlower
specificationlimit(LSL)foraparticularprocessorproducts.Using
USL LSL sample mean and standard deviation both Cp and Cpk
USL,LSL,samplemeanandstandarddeviation,bothCpandCpk
indexescanbecalculated.
April 15, 2014

Dr. Mehdizadeh
77

Step4
TodetermineCpindex,subtracttheLSLfromUSL(USLLSL)and
divide the value by six times of the standard deviation (6 x standard
dividethevaluebysixtimesofthestandarddeviation(6xstandard
deviation).
Cp=(USLLSL)/6xstandarddeviation.
April 15, 2014

Dr. Mehdizadeh
78

Step5
DetermineCpu andCpltocalculateCpk index.
Cpu istheindexofthetotalprocessvariationwithrespecttoupper
specificationlimit(USL)andCplistheindexofthetotalprocess
variationassociatedwithlowerspecificationlimit(LSL).
AfterdeterminingCpu
After determining Cpu andCpl,whicheverresultsinthesmallest
and Cpl, whichever results in the smallest
value istheCpk index.
Cpu =(USLsamplemean)/3xstandarddeviation.
= (USLsample mean)/3x standard deviation
Cpl=(LSLsamplemean)/3xstandarddeviation.
April 15, 2014

Dr. Mehdizadeh
79
Cpk
p Cp
p

Cpk Cp
.
Inqualitymanagement,Cp isgenerallywithhighervalue comparedto
Cpk withtheconsiderationthattheprocessisnotcentered withinthe
specificationlimits.
Cpk
. Cp
TheCpk indexcanchange intheprocessbyadjustingthecenteringof
theprocess;however,Cpalwaysremainsthesameunless anychangeis
madeonprocessitself.
April 15, 2014

Dr. Mehdizadeh
80
Cpk
C t Off
CutOffs
Cpk > 1.33
)(
MotorolasSixSigmaQuality
Cp=2.00,andCpk =1.50
PPM=3.4

1<Cpk <1.33
)( . 1.33 1
)( .
Cp>1
.
81

Dr. Mehdizadeh
April 15, 2014

Automated Control Charts
AutomatedControlCharts
April 15, 2014

Dr. Mehdizadeh
82
SixSigma

April 15, 2014

Dr. Mehdizadeh
83

Definition Six Sigma
DefinitionSixSigma
:(
)

SixSigma(instatistics):
Si Si
(i
i i )
thedefinitionofoutcomesascloseaspossibletoperfection.
99.9997 3.4
Withsixstandarddeviations,wearriveat3.4defectspermillion
opportunities,or99.9997percent,

.

soreachingSixSigmameansthatyourprocessorproductwill
performwithalmostnodefects.
performwithalmostnodefects
April 15, 2014

Dr. Mehdizadeh
84

Definition Six Sigma
DefinitionSixSigma

SixSigma(asaphilosophy):
g
(
p
p y)

isatotalmanagementcommitmentandphilosophyofexcellence,
customerfocus,processimprovement,andtheruleof
measurement.
April 15, 2014

Dr. Mehdizadeh
85

The Classical View of Performance
TheClassicalViewofPerformance
SixSigmaisaphilosophy:
Whyisnt 99%acceptablegoodenough...??
15minuteseachdayofunsafedrinkingwater.
5,000incorrectsurgicalproceduresperweek.
4ormoreaccidentsperdayatmajorairports.
200,000wrongdrugprescriptionseachyear.
200,000 wrong drug prescriptions each year.
7hourseachmonthwithoutelectricity.
Long-Term
Long
Term Yield
3 Sigma Process Capability
93.32%
Historical Standard
99.38%
Current Standard
99.99966%
World-Class
World
Class
April 15, 2014

Dr. Mehdizadeh
86

Hi t
History
of6Sigma
f 6 Si

6Sigmamanufacturingphilosophy camefromMotorola

Theyrecognisedthatsufficientprocessimprovementwouldnotoccurusing
a conventional approach to quality.
aconventionalapproachtoquality.

Itwasdevelopedtohelpthemreducevariationwithinaprocess byfocusing
effortonimprovinginputstoaprocess ratherthanreacting tooutputs.
On target, minimum process variation
April 15, 2014

Dr. Mehdizadeh
87

6 Sigma
6Sigma

Theprocesswasfailingthecustomerexpectations
4 3
1.33 1.0 Cpk
. % 99.3 %93
Traditionally,
Traditionally,processesaimedforprocesscapabilityof3to4sigma
processes aimed for process capability of 3 to 4 sigma
(Cpk =1.0to1.33or93%to99.3%acceptable)
)( 6200
Thecustomerreceived6200defectiveproductpermillionatbest
Cpk=2 6
P
Processesnowaimfor6sigma(Cpk=2)
i f 6 i
(C k 2)
. 3.4
Thecustomerwouldreceive3.4
The customer would receive 3 4 defectiveproductpermillion
defective product per million
April 15, 2014

Dr. Mehdizadeh
88
Cpk
p

April 15, 2014

Dr. Mehdizadeh
89
6
6sigmaProcessCapability
g
p
y
Whatisit(CPK)
3Sigma(Processcapabilityof1CPK)
3 Sigma ( Process capability of 1 CPK )

if the process (lorry) slightlyvariesthenthescrapordamagewilloccur
slightly varies then the scrap or damage will occur
iftheprocess(lorry)
6Sigma(Processcapabilityof2CPK)
if the process (lorry) varies, there will be no scrap or damage
iftheprocess(lorry)varies,therewillbenoscrapordamage
Curbs=
requiredprocesstolerances
CPKof1
(3 sigma)
(3sigma)
April 15, 2014
CPKof2
(6 i
(6sigma)
)
Dr. Mehdizadeh
90
April 15, 2014

Dr. Mehdizadeh
91
Evaluation of blistering
g process
p
in XXX Pharmaceutical
Company
April 15, 2014

Dr. Mehdizadeh
92
Analyze
1 Cause and effect diagram
1.Causeandeffectdiagram
April 15, 2014

Dr. Mehdizadeh
93
April 15, 2014

Dr. Mehdizadeh
94

Improvement methodology
Improvementmethodology
DMAIC
Define
Measure
Analyze
Improve
Control
April 15, 2014

Dr. Mehdizadeh
95
How do we fill this quality gap

in the pharmaceutical industry?
Sigma ppm Defects

Current Mfg
Quality provided
to patients
2
3
4
5
6
308,537
66,80
80
66
66,807
807
76,210
233
3.4
Yield
Cost of Quality
69.2%
93 3%
93.3%
99.4%
99.98%
99.99966%
25-35%
20 25%
20-25%
12-18%
4-8%
1-3%
by testing !!!!
Data from: Dr. Doug Dean & Frances Bruttin
PriceWaterhouseCoopers
Slide 96 May 2008

66745579
66745578
97

Dr. Mehdizadeh
April 15, 2014

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