2. •Fare clic per modificare stili del testo dello schema
–Secondo livello
•Terzo livello
–Quarto livello
»Quinto livello
2Scenario
Pharma Company Specifications
Container
Vial
Size (ml)
15
Glass Type
Tube
Glass Color
Transparent
Diameter(mm)
21
Product Fill
Empty,Lyophilized
Headspace Pressure (mbar)
[3-80] mbar
Headspace Gas
Air
Capacity (#/hour)
> 18000
3. •Fare clic per modificare stili del testo dello schema
–Secondo livello
•Terzo livello
–Quarto livello
»Quinto livello
3Standard Samples Set Implementation
EquipmentLF-HG:
UsedtoimplementStandardSamples
FinishedVialswithcertifiedheadspaceconditions
AutomaticStoppering
4. •Fare clic per modificare stili del testo dello schema
–Secondo livello
•Terzo livello
–Quarto livello
»Quinto livello
4Reference Sample Set Build Up
Container
Samples Number
ID
FIll
HeadspaceTotal Pressure(*)[mbara]
OxygenPartial Pressure [mbara]
Oxygenconcentration [%]
15 ml
Ø 21 mm
Tube
Transparent
4
F1
Empty
3
0,6
0,06
1
F2
Lyo
5
1
0,10
1
F3
Empty
10
2,1
0,21
1
F4
Empty
20
4,2
0,42
1
F5
Empty
40
8,3
0,83
1
F6
Empty
80
16,6
1,66
(*) Hypothesis: air consists of 20,8 % of Oxygen
5. •Fare clic per modificare stili del testo dello schema
–Secondo livello
•Terzo livello
–Quarto livello
»Quinto livello
5Equipment used in the Case Studies
Mock-UpSystem:
Referencecontainersindividuallynumberedandloadedintherotarystarwheel
HeadspaceOxygenAnalysis
Productionspeedvariedaccordinginspectiontime
LaserUnitpositionadjustedfortheheightoftheContainers
6. •Fare clic per modificare stili del testo dello schema
–Secondo livello
•Terzo livello
–Quarto livello
»Quinto livello
6Performance Indicators
σ–SigmaLevel
Measuresthecapabilityoftheprocesstoperformdefect-free
P(%)–ProbabilityofoccurrenceofFalseResults
FalseNegative
FalsePositive
IR(O2Concentration)–InspectionResolution
MeasuresthecapabilitytodistinguishbetweendifferentheadspaceO2concentrations
7. •Fare clic per modificare stili del testo dello schema
–Secondo livello
•Terzo livello
–Quarto livello
»Quinto livello
7
σLevel and P
σ–Sigma Level
P (%)
Defective ppm
1
31,73
317300
2
4,55
45500
3
0,27
270
4
0,0063
63
5
0,000057
0,57
6
0,0000002
0,002
-1σ
-2σ
-3σ
-4σ
-6σ
-5σ
6σ
5σ
4σ
3σ
1σ
2σ
Mean
8. •Fare clic per modificare stili del testo dello schema
–Secondo livello
•Terzo livello
–Quarto livello
»Quinto livello
9False Results Assessment, an example
Hp:TargetO2Concentration
0,06%-Conforming
0,82%-Defective
Whatistheprobabilityofoccurrence:
1.FalseNegative
2.FalsePositive
9. •Fare clic per modificare stili del testo dello schema
–Secondo livello
•Terzo livello
–Quarto livello
»Quinto livello
10
σSigma Level Calulation
Anderson-Darling Normality Test
If P-Value > 0,05 Data are normally distributed Sigma Level meaningful
10. •Fare clic per modificare stili del testo dello schema
–Secondo livello
•Terzo livello
–Quarto livello
»Quinto livello
11Case 1 –Method Overview
Container Data
Item
Description
15 mlØ 21 mm,
Tube, Transparent, [F1,F2, F3, F4, F5, F6]
Equipment
Mock-up
Motion
Continuous
Inspection time
5 time points:
•100ms, 200ms, 224ms,300ms,400ms
Number of HGA inspections per unit
100
Test period
Over 1 day
N2Purging
Not required
11. •Fare clic per modificare stili del testo dello schema
–Secondo livello
•Terzo livello
–Quarto livello
»Quinto livello
12Case 1 –Activities
Anderson-Darlingtestpassed
F6,F5andF4inturntakenasareferenceofnonconformingcontainers
PerformanceIndicatorscalculated:
ProcessSigmaLevel
ProbabilityofOccurrenceofFalseResults
InspectionResolution
ID
HeadspaceTotal Pressure(*) [mbara]
Oxygenconcentration [%]
F1
3
0,06
F2
5
0,10
F3
10
0,21
F4
20
0,42
F5
40
0,83
F6
80
1,66
12. •Fare clic per modificare stili del testo dello schema
–Secondo livello
•Terzo livello
–Quarto livello
»Quinto livello
13Case 1 –Findings (1)
Format ID
Value
InspectionTime
100 ms
200 ms
224 ms
300 ms
400 ms
F1
Mean
51,31
50,63
50,66
50,37
50,37
StdDev
1,34
1,00
0,87
0,76
0,70
F2
Mean
52,90
51,85
50,86
50,46
51,17
StdDev
1,77
1,16
1,15
1,12
1,02
F3
Mean
55,27
54,37
54,19
54,17
54,34
StdDev
1,37
0,97
0,98
0,84
0,70
F4
Mean
59,27
58,43
58,36
58,32
58,63
StdDev
1,40
1,11
1,04
0,83
0,78
F5
Mean
69,22
68,56
68,42
68,07
67,71
StdDev
1,28
1,16
1,08
0,92
1,01
F6
Mean
84,39
83,98
84,16
83,86
84,40
StdDev
1,33
1,13
0,89
0,81
0,76
13. •Fare clic per modificare stili del testo dello schema
–Secondo livello
•Terzo livello
–Quarto livello
»Quinto livello
14Case 1 –Findings (2)
IR (%)
Reference
InspectionTime
σ– Sigma Level
100 ms
200 ms
224 ms
300 ms
400 ms
1,60
F1-F6
12,36
12,66
12,65
12,75
12,75
1,56
F2-F6
8,92
12,20
12,57
12,72
12,45
1,46
F3-F6
10,66
11,25
11,32
11,33
11,27
1,25
F4-F6
8,98
9,73
9,76
9,77
9,66
0,83
F5-F6
5,69
5,93
5,99
6,12
6,25
0,77
F1-F5
6,69
7,25
7,24
7,35
7,35
0,73
F2-F5
4,62
6,77
7,16
7,32
7,04
0,62
F3-F5
5,11
5,79
5,86
5,87
5,80
0,42
F4-F5
3,56
4,21
4,24
4,25
4,13
0,35
F1-F4
2,84
3,09
3,08
3,18
3,18
0,31
F2-F4
1,80
2,65
3,00
3,15
2,89
0,21
F3-F4
1,43
1,75
1,81
1,82
1,76
14. •Fare clic per modificare stili del testo dello schema
–Secondo livello
•Terzo livello
–Quarto livello
»Quinto livello
15Case 1 –Findings (3)
IR (%)
Reference
InspectionTime
P (%)
100 ms
200 ms
224 ms
300 ms
400 ms
1,60
F1-F6
0
0
0
0
0
1,56
F2-F6
0
0
0
0
0
1,46
F3-F6
0
0
0
0
0
1,25
F4-F6
0
0
0
0
0
0,83
F5-F6
0
0
0
0
0
0,77
F1-F5
2,2*10^-11
0
0
0
0
0,73
F2-F5
4*10^-3
1,2*10^-9
8,1*10^-11
2,5*10^-11
1,9*10^-10
0,62
F3-F5
3*10^-5
6,9*10^-7
4,6*10^-7
4,3*10^-7
6,5*10^-7
0,42
F4-F5
0,04
2,5*10^-3
2,2*10^-3
2,1*10^-3
3,6*10^-3
0,35
F1-F4
0,45
0,20
0,21
0,15
0,15
0,31
F2-F4
7,14
0,81
0,27
0,17
0,38
0,21
F3-F4
15,30
8,02
6,99
6,84
7,83
15. •Fare clic per modificare stili del testo dello schema
–Secondo livello
•Terzo livello
–Quarto livello
»Quinto livello
16Case 1 –Findings (4)
InspectionTime
(ms)
Equivalent (*)
Production Speed(cpm)
100
334
200
167
224
149
300
111
400
84
(*) 1 Laser unit installed
16. •Fare clic per modificare stili del testo dello schema
–Secondo livello
•Terzo livello
–Quarto livello
»Quinto livello
17Case 2 –Method Overview
Container Data
Item
Description
15 mlØ 21 mm,
Tube, Transparent, [F1, F1_1_L, F1_2_L, F1_3_L]
Equipment
Mock-up
Motion
Continuous
Inspection time
5time points:
•100ms, 200ms, 224ms,300ms,400ms
Number of HGA inspections per unit
100
Test period
Over 1 day
N2Purging
Not required
17. •Fare clic per modificare stili del testo dello schema
–Secondo livello
•Terzo livello
–Quarto livello
»Quinto livello
18
100HGAinspectionsof4samplesofthesetF1
Foundconsistencybetweenindividualresults
Actions:
0,215ccofairinjectedintoF1_1_L
0,3ccofairinjectedintoF1_2_L
0,4ccofairinjectedintoF1_3_L
After1minuteintervalF1_1_L,F1_2_L,F1_3_Linspectedagain100timesCase 2 –Activities
Format ID
Value
InspectionTime
224 ms
F1
Mean
51,33
StdDev
0,95
F1_1_L
Mean
51,18
StdDev
0,88
F1_2_L
Mean
51,94
StdDev
0,95
F1_3_L4
Mean
51,26
StdDev
0,98
18. •Fare clic per modificare stili del testo dello schema
–Secondo livello
•Terzo livello
–Quarto livello
»Quinto livello
19
Airinjectedinthecontainersimulatesaleakageoveratimeinterval
Directcorrelationbetweenflowrateovertimeandorificesize
Hp:
TimeintervalT=1min
Pressuredifferentialbetweencontainerinside&outsideΔP1bar
Leakage/orificesize:
0,215cc5μm
0,3cc5.92μm
0,4cc6.85μmCase 2 –Flow Rate VS Hole Size
19. •Fare clic per modificare stili del testo dello schema
–Secondo livello
•Terzo livello
–Quarto livello
»Quinto livello
20
Whathappens:
PressureriseresultingfrompinholesCase 2 –HeadspaceLeakRate Model
HeadspaceTotal Pressure [mbara]
OxygenPartial Pressure [mbara]
LeakageRate (cc)
0,215
0,30
0,40
14,52
0,30%
60
43
32
20,26
0,42%
84
60
45
27,01
0,56%
112
80
60
Time (sec)
20. •Fare clic per modificare stili del testo dello schema
–Secondo livello
•Terzo livello
–Quarto livello
»Quinto livello
21Case 2–Findings (1)
Air Injected(cc)
Reference
TimePoints
σ– Sigma Level
100 ms
200 ms
224 ms
300 ms
400 ms
0,215
F1-F1_1_L
4,39
4,33
4,37
4,34
4,47
0,3
F2-F1_2_L
6,36
6,27
6,17
6,18
6,29
0,4
F3-F1_3_L
7,42
7,41
7,35
7,42
7,58
Results:
Aleakageof5μmcanbedetectedat>4,3sigmalevel
Aleakageof6μmcanbedetectedat>6,1sigmalevel
Aleakageof7μmcanbedetectedat>7,3sigmalevel
InspectionTime
P (%)
1,1*10^-3
1,5*10^-3
1,2*10^-3
1,4*10^-3
7*10^-4
2*10^-8
3,6*10^-8
6,6*10^-3
6,5*10^-8
3,1*10^-8
0
0
0
0
0
21. •Fare clic per modificare stili del testo dello schema
–Secondo livello
•Terzo livello
–Quarto livello
»Quinto livello
22Case 2–Findings (2)
Air Injected(cc)
InspectionTime
Equivalent Air Flow (cc/min)
Equivalent Hole Size (μm)
100 ms
200 ms
224 ms
300 ms
400 ms
0,215
35
36
35
36
34
0,126
3,84
0,3
25
26
25
26
24
0,126
3,84
0,4
19
19
19
19
18
0,126
3,84
Split Time (sec)
Results:
Aleakageof3,9μmcanbedetectedat>3sigmalevel
Timeneededfora3sigmaprocess
22. •Fare clic per modificare stili del testo dello schema
–Secondo livello
•Terzo livello
–Quarto livello
»Quinto livello
24Thank you! Questions & Comments?