The document discusses specifications for leak testing and inspection of pharmaceutical vials. It describes the container specifications including size, glass type, color, diameter and fill requirements. It outlines two test cases where multiple vials with varying headspace pressures were inspected to analyze the inspection resolution and process capability at different inspection times. In the second case, small amounts of air were injected into vials to simulate leakage over time, and inspection results showed the system could detect leaks of approximately 5-7 microns.

1. Leak Testing and Inspection Machinery

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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

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3Standard Samples Set Implementation
EquipmentLF-HG:
UsedtoimplementStandardSamples
FinishedVialswithcertifiedheadspaceconditions
AutomaticStoppering

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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

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5Equipment used in the Case Studies
Mock-UpSystem:
Referencecontainersindividuallynumberedandloadedintherotarystarwheel
HeadspaceOxygenAnalysis
Productionspeedvariedaccordinginspectiontime
LaserUnitpositionadjustedfortheheightoftheContainers

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6Performance Indicators
σ–SigmaLevel
Measuresthecapabilityoftheprocesstoperformdefect-free
P(%)–ProbabilityofoccurrenceofFalseResults
FalseNegative
FalsePositive
IR(O2Concentration)–InspectionResolution
MeasuresthecapabilitytodistinguishbetweendifferentheadspaceO2concentrations

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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

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9False Results Assessment, an example
Hp:TargetO2Concentration
0,06%-Conforming
0,82%-Defective
Whatistheprobabilityofoccurrence:
1.FalseNegative
2.FalsePositive

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10
σSigma Level Calulation
Anderson-Darling Normality Test
If P-Value > 0,05 Data are normally distributed Sigma Level meaningful

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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

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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

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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

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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

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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

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16Case 1 –Findings (4)
InspectionTime
(ms)
Equivalent (*)
Production Speed(cpm)
100
334
200
167
224
149
300
111
400
84
(*) 1 Laser unit installed

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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

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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

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19
Airinjectedinthecontainersimulatesaleakageoveratimeinterval
Directcorrelationbetweenflowrateovertimeandorificesize
Hp:
TimeintervalT=1min
Pressuredifferentialbetweencontainerinside&outsideΔP1bar
Leakage/orificesize:
0,215cc5μm
0,3cc5.92μm
0,4cc6.85μmCase 2 –Flow Rate VS Hole Size

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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)

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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
Aleakageof6μmcanbedetectedat>6,1sigmalevel
Aleakageof7μmcanbedetectedat>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

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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

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24Thank you! Questions & Comments?