Leak Testing and Inspection Machinery
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Scenario
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
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Standard Samples Set Implementation
Equipment LF-HG:
Used to implement Standard Samples
Finished Vials with certified headspace conditions
Automatic Stoppering
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Reference Sample Set Build Up
ContainerSamples Number
ID FIllHeadspace Total
Pressure(*) [mbara]
Oxygen Partial
Pressure [mbara]
Oxygen
concentration [%]
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
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Equipment used in the Case Studies
Mock-Up System:
Reference containers individually
numbered and loaded in the rotary star
wheel
Headspace Oxygen Analysis
Production speed varied according
inspection time
Laser Unit position adjusted for the
height of the Containers
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Performance Indicators
σ – Sigma Level
Measures the capability of the process to perform defect-free
P (%) – Probability of occurrence of False Results
False Negative
False Positive
IR (O2 Concentration) – Inspection Resolution
Measures the capability to distinguish between different headspace O2
concentrations
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σ Level and P
σ – Sigma
LevelP (%)
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 6σ5σ4σ3σ1σ 2σMean
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False Results Assessment, an example
Hp: Target O2 Concentration
0,06% - Conforming
0,82% - Defective
What is the probability of
occurrence:
1. False Negative
2. False Positive
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σ Sigma Level Calulation
Anderson-Darling Normality Test
If P-Value > 0,05 Data are normally distributed Sigma Level meaningful
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Case 1 – Method Overview
Container Data Item Description
15 ml Ø 21 mm,Tube, Transparent,[F1, F2, F3, F4, F5,
F6]
Equipment Mock-up
Motion Continuous
Inspection time5 time points: • 100ms, 200ms, 224ms, 300ms, 400ms
Number of HGA inspections per unit 100
Test period Over 1 day
N2 Purging Not required
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Case 1 – Activities
Anderson-Darling test passed
F6, F5 and F4 in turn taken as a reference
of non conforming containers
Performance Indicators calculated:
Process Sigma Level
Probability of Occurrence of False Results
Inspection Resolution
ID
Headspace
Total
Pressure(*)
[mbara]
Oxygen
concentration
[%]
F1 3 0,06
F2 5 0,10
F3 10 0,21
F4 20 0,42
F5 40 0,83
F6 80 1,66
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Case 1 – Findings (1)
Format ID ValueInspection Time
100 ms 200 ms 224 ms 300 ms 400 ms
F1Mean 51,31 50,63 50,66 50,37 50,37
StdDev 1,34 1,00 0,87 0,76 0,70
F2Mean 52,90 51,85 50,86 50,46 51,17
StdDev 1,77 1,16 1,15 1,12 1,02
F3Mean 55,27 54,37 54,19 54,17 54,34
StdDev 1,37 0,97 0,98 0,84 0,70
F4Mean 59,27 58,43 58,36 58,32 58,63
StdDev 1,40 1,11 1,04 0,83 0,78
F5Mean 69,22 68,56 68,42 68,07 67,71
StdDev 1,28 1,16 1,08 0,92 1,01
F6Mean 84,39 83,98 84,16 83,86 84,40
StdDev 1,33 1,13 0,89 0,81 0,76
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Case 1 – Findings (2)
IR (%) ReferenceInspection Time
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
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Case 1 – Findings (3)
IR (%) ReferenceInspection Time
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
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Case 1 – Findings (4)
Inspection
Time
(ms)
Equivalent (*)
Production
Speed (cpm)
100 334
200 167
224 149
300 111
400 84
(*) 1 Laser unit installed
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Case 2 – Method Overview
Container Data Item Description
15 ml Ø 21 mm,Tube, Transparent,
[F1, F1_1_L,F1_2_L, F1_3_L]
Equipment Mock-up
Motion Continuous
Inspection time5 time points: • 100ms, 200ms, 224ms, 300ms, 400ms
Number of HGA inspections per unit 100
Test period Over 1 day
N2 Purging Not required
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100 HGA inspections of 4 samples of the set F1
Found consistency between individual results
Actions:
0,215 cc of air injected into F1_1_L
0,3 cc of air injected into F1_2_L
0,4 cc of air injected into F1_3_L
After 1 minute interval F1_1_L, F1_2_L, F1_3_L inspected again 100 times
Case 2 – Activities
Format
IDValue
Inspection
Time
224 ms
F1Mean 51,33
StdDev 0,95
F1_1_LMean 51,18
StdDev 0,88
F1_2_LMean 51,94
StdDev 0,95
F1_3_L4Mean 51,26
StdDev 0,98
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Air injected in the container simulates a leakage over a time interval
Direct correlation between flow rate over time and orifice size
Hp:
Time interval T = 1 min
Pressure differential between container inside & outside ΔP 1 bar
Leakage / orifice size:
0,215 cc 5 µm
0,3 cc 5.92 µm
0,4 cc 6.85 µm
Case 2 – Flow Rate VS Hole Size
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What happens:
Pressure rise resulting from pinholes
Case 2 – Headspace Leak Rate Model
Headspace
Total
Pressure
[mbara]
Oxygen
Partial
Pressure
[mbara]
Leakage Rate (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)
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Case 2 – Findings (1)
Air Injected (cc) Reference
Time Points
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:
A leakage of 5 µm can be detected at > 4,3 sigma level
A leakage of 6 µm can be detected at > 6,1 sigma level
A leakage of 7 µm can be detected at > 7,3 sigma level
Air Injected (cc) Reference
Inspection Time
P (%)
100 ms 200 ms 224 ms 300 ms 400 ms
0,215 F1-F1_1_L 1,1*10^-3 1,5*10^-3 1,2*10^-3 1,4*10^-3 7*10^-4
0,3 F2-F1_2_L 2*10^-8 3,6*10^-8 6,6*10^-3 6,5*10^-8 3,1*10^-8
0,4 F3-F1_3_L 0 0 0 0 0
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Case 2 – Findings (2)
Air
Injected
(cc)
Inspection TimeEquivalent 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:
A leakage of 3,9 µm can be detected at > 3 sigma level
Time needed for a 3 sigma process
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Thank you!
Questions & Comments?