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Current Practice, Common Mistakes, New Developments By Dana Morton Guazzo, PhD
RxPax, LLC Bridgewater, NJ 08807 dguazzo@rxpax.com
Summary
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Current leak testing and package development practices are ineffective in preventing major recalls
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Validation studies have shown a lack of sensitivity and reliability For example
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0.1% aq. Methylene Blue -27 KPa 10 min 30 min -25 KPa 30 min 30 min Visual inspection
H. Wolf, et al, PDA J Pharm Sci & Technol., 63, 2009, p. 489 - 498
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Logistics
3 Test sites, 3 Inspection stations, 10 Inspectors 10 sec pacing, randomized, blinded Inspection stations varied: lighting type, intensity, position, background angle and position
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Test Samples
Negative Controls
No No No No No
5 m
No No No No No
10 m
15 m
H. Wolf, et al, PDA J Pharm Sci & Technol., 63, 2009, p. 489 - 498
Negative Controls
5 m
10 m
15 m
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H. Wolf, et al, PDA J Pharm Sci & Technol., 63, 2009, p. 489 - 498
Test Samples
Negative Controls
No No No No No
5 m
No No No No No
10 m
15 m
H. Wolf, et al, PDA J Pharm Sci & Technol., 63, 2009, p. 489 - 498
Test Samples
Negative Controls
No No No No Yes
5 m
10 m
15 m
H. Wolf, et al, PDA J Pharm Sci & Technol., 63, 2009, p. 489 - 498
Negative Controls 10 m
15 m
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H. Wolf, et al, PDA J Pharm Sci & Technol., 63, 2009, p. 489 - 498
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Destructive method
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Part 3
Best Practices Leak Test Methods Validation Concepts
Reliable
Proven using a random mix of positive (with-leak) and negative (no-leak) controls
Therefore, positive control test samples with leaks of appropriate size and type are required
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D. Guazzo, Package Integrity Testing Chapter 4, Parenteral Quality Control, 2nd Ed.,Marcel Dekker, NYC, 1994
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Challenge conditions
Airlock elimination procedure
Water bath immersion 60C 2hr, then 25C 1hr
Kirsch, et al, PDA J Pharm Sci & Technol 51, 5, 1997 p. 188
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No ingress
Log -5 to -5.8 sccs ~0.3 to 0.2m
Kirsch, et al, PDA J Pharm Sci & Technol 51, 5, 1997 p. 200
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Challenge medium
Liquid Liquid Aerosol
Challenge microbe
P. diminuta E. coli E. Coli P. Fragi
Challenge path
Glass micro-pipette Poly-coated glass micro-tube Nickel micro-tube
Challenge conditions
Airlock elimination step + 24 hr ambient ISO closure reseal: 30 min 22Hg + 30 min ambient Varied: -20 kPa to +20 kPa 4 to 37C
0.3 m 10 m 5 m
Burrell
JPDA 2000
Keller
J Applied Pkgg Res 2006
Critical leak threshold ranged from 0.3 to 10m Leak path liquid presence is required for microbial ingress > Liquid flow = > microbial ingress potential
Liquid presence does not guarantee microbial ingress
real leaks
Real leak paths are not holes, tubes, pipettes
Natural defects are long, complex, irregular channels Defects consist of actual package materials
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2007
0.5 to 15 m
10 to 120 m
Mass spectrometry
108 cfu/mL - 0.4 bar 1 hr + 0.4 bar 1 hr
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Morrical, et al, PDA J Pharm Sci & Technol 61, 2007 p. 226 236
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Morrical, et al, PDA J Pharm Sci & Technol 61, 2007 p. 226 236
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Morrical, et al, PDA J Pharm Sci & Technol 61, 2007 p. 226 236
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Holed vial helium flow matched theoretical predictions for orifice Wired vial helium flow followed less predictable, more complex dynamics
Morrical, et al, PDA J Pharm Sci & Technol 61, 2007 p. 226 236
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Location
Above and below product-fill level As close to critical seal area as possible
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Benefit
Verifies ability of CCI method to find defects likely to occur Greatest benefit during method development studies Size Exact sizing may not be feasible Type defects are often large leaks Ironically, larger defects are the cause for product recalls
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Channel defect
Positive controls
Product-filled with-defect packages Used to verify actual leaking package detection capability
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Product- or placebo-filled
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Part 4
Best Practices Leak Test Methods
Proven Nondestructive Methods
Test methods
1. 2. 3.
Vacuum decay High voltage leak detection (HVLD) Laser-based headspace detection (FMS)
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1. Vacuum Decay
For dry or liquid products, most package systems Detects pressure rise from gas or vapor egress Limitations
Protein clogging often prevents leak detection Liquid leaks may contaminate test chamber
Considerations
Faster tests limit sensitivity Instrument design/make can influence test results
Transducers and internal system design No-leak baseline stability
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ASTM F2338-09
Test Method Sequence of Events 1a. Vacuum drawn during FILL Time
1000 Torr Transducer (mbar)
1b. Vacuum source is shut OFF 2. Pressure rise monitored during EQUALIZATION and TEST Times
1000 Torr Transducer (mbar)
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Logistics
3 Test sites Amgen, BMS, PTI 3 Instruments PTI VeriPac 325-LV 3 Replicates of ea. study at ea site, 2 days per site Samples randomized within ea. study
H. Wolf, et al, PDA J Pharm Sci & Technol., 63, 2009, p. 477 - 488
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ASTM F2338-09
Vacuum decay test parameters
Leak test parameters
Evacuation (Fill) time Equalization time Test time Pressure rise reference limit 1000 Torr transducer Pressure rise reference limit 10 Torr transducer
Parameter limits
6s 0.2 s 8s 2 mbar (abs) 25 Pa (differential)
20 15 10 5 0 -5 0
0 0
20
40
Site 1: 0-45
60
80
100
120
140
Study 4, Water-filled Syringes for Gas Leak Tests Study 5, Water-filled Syringes for Liquid Leak Tests dP Ref Pass/Fail Limit
H. Wolf, et al, PDA J Pharm Sci & Technol., 63, 2009, p. 477 - 488
Study No. Packages Tested No. Tests No. FAILED No. PASSED % Accurate
15 15
135 134
0 0
135 134
100 100
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Vacuum Decay Liquid Leak Test Positive control syringes Air-filled vs Water-filled Syringes Air- vs. water-filled
200 180 160 140 dP (Pa) 120 100 80 60 40 20 0 4.6 4.7 4.8 4.9 5 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 Nominal Hole Size (microns)
A water-filled 5.7 m unit gave 1 ABORT result (not graphed)
Vacuum decay
Nominal 5 m holes
H. Wolf, et al, PDA J Pharm Sci & Technol., 63, 2009, p. 477 - 488
Syringe Contents No. Packages Tested No. Tests No. FAILED No. PASSED % Accurate
15 15
45 45
45 45
0 0
100 100
60
200 100
0 7 8 9 10 11 12 13 14 15 16 17 Nominal Hole Size (microns) Study 4, Air-filled Syringes Study 5, Water-filled Syringes dP Ref Pass/Fail Limit
Syringe Contents
No. Tests
No. FAILED
No. PASSED
% Accurate
30 30
90 90
90 90
0 0
100 100
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Test Samples
Air-filled Syringe
Vac decay
dP (Pa)
Pass or Fail
Negative Controls
11 10 12 9 9
5 m
25
(4.7 m) 71 80 43 42
10 m
15 m
RxPax, LLC, PDA Metro Chapter, May 2011 281 Yes Yes
H. Wolf, et al, PDA J Pharm Sci & Technol., 63, 2009, p. 489 - 498
Test Samples
Air-filled Syringe
Vac decay
dP (Pa) Pass or Fail
Negative Controls
7 6 7 6 7
5 m
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(4.7 m) 66 79 44 42
10 m
15 m
301 Yes RxPax, LLC, PDA Metro Chapter, May 2011 Yes
H. Wolf, et al, PDA J Pharm Sci & Technol., 63, 2009, p. 489 - 498
Test Samples
Air-filled Syringe
Vac decay
dP (Pa) Pass or Fail
Negative Controls
9 9 10 9 17
5 m
57 96 43 41 51
10 m
15 m
ABORT LLC, PDA Metro Chapter, May 2011 Yes Yes RxPax,
H. Wolf, et al, PDA J Pharm Sci & Technol., 63, 2009, p. 489 - 498
Detects liquid present near leak path Fast, clean test method Considerations
Method-product compatibility to be checked Whole package vs. spot location checks Package rotation to capture leaks in headspace region Instrument make/design can influence test results
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Project scope
ID defects sources, risk of propagation and leakage ID a nondestructive leak test able to find such defects in finished product packages
Aqueous solution formulations 20mm elastomeric serum stopper 20mm aluminum flip seal
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Vial 4
Vial 6
Vial 5
Vial ID code
Analyzed by
AGR, GPT
Description
Large split
Propagation risk
Moderate to high under certain handling conditions
Leakage risk
Very likely
4, 5, 6
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Vial 8
Vial 7
Vial ID code
Analyzed by
AGR GPT
Description
Smaller split Open check or chip Rough surface Unfilled finish flaw Rough surface Plunger mark
Propagation risk
Not likely Possible, may lead to split finish Not likely Not likely
Leakage risk
Possible if not capped properly Possible if finish splits Possible if not capped properly Possible if not capped properly
AGR GPT
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Vial 9
Vial 10
Vial 9
Vial 10
Vial ID code
Analyzed by
AGR GPT
Description
Neck ring seams Knockout on inside lip Mismatched neck ring seam, Plunger mark Somewhat healed split finish
Propagation risk
Not likely Healed split finish might extend
Leakage risk
Not likely Possible if finish split opens
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Vial 11
Vial 13
Vial 12
Vial ID code
Analyzed by
AGR GPT
Description
Neck ring seams Knockout on inside lip Mismatched neck ring seam, Plunger mark Somewhat healed split finish
Propagation risk
Not likely Healed split finish might extend
Leakage risk
Not likely Possible if finish split opens
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Vial 3
Vial ID code
Analyzed by
AGR GPT
Description
Fold defect Loading mark defect or knockout defects Heavy lap in neck
Propagation risk
Not likely Small risk
Leakage risk
Not likely Not likely 72
Vial 1
Vial 2
Vial 1
Vial ID code
Analyzed by
AGR GPT
Description
Fold defect Loading mark defect or knockout defects Laps Mismatched and/or heavy neck ring seams Cords, Loading marks
Propagation risk
Not likely Not likely
Leakage risk
Not likely Not likely
1, 2
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Land channel
Valve channel
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Test chamber
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Package contents
Artificial defects: 1/2 = active product 1/2 = placebo Natural defects all contained active product
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Vacuum decay
10 8 10 9 10 10
HVLD
10 10 10 10 10 10
15
25
Placebo Active
50
Placebo Active
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Vacuum decay
0 0 0 0 10 10
HVLD
0 2* 0 0 10 10
None Valve
Placebo Active
Land + Valve
Placebo Active
* Second HVLD failure was confirmed for a total of 5 HVLD tests. Both packages demonstrated HVLD char marks across vial and stopper land surfaces.
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continued
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5, 6 8 7
Large split Smaller split Open check or chip Rough surface Unfilled finish flaw Rough surface Plunger mark
Very likely Possible if not capped properly Possible if finish splits Possible if not capped properly Possible if not capped properly
5 -------
5, 6 8 -----
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HVLD -----
-----
Fold defect Loading mark defect or knockout defects Heavy lap in neck
Not likely
---
---
-----
-----
1, 2
Fold defect Loading mark defect or knockout defects Laps Mismatched and/or heavy neck ring seams Cords, Loading marks
Not likely
---
---
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However,
HVLD detected a larger % of potential leaking packages
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Test samples
Vials - laser drilled holes (15, 25, 50 ) Packages contained either Proteinaceous active product solution Placebo solution
Experiment
Samples leak tested in random order on days 1 and 29 Vacuum decay first, then HVLD on each test day
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DAY 1
Vacuum decay HVLD
DAY 29
Vacuum decay HVLD
PRODUCT-FILLED
15 25 50 10 10 10 8 9 10 10 10 10 2 2 3 10 10 10
PLACEBO-FILLED
15 25 50 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10
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Test samples
Three different proteinaceous active products
Experiment
Product exposed to HVLD at 25kV 0x,
1x, 10x
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Product A
Monomeric Peak Rel. MW % Purity High MW Species % Purity Low MW Species % Purity
Product B
Monomeric Peak Rel. MW % Purity High MW Species % Purity Low MW Species % Purity
Product C
Monomeric Peak Rel. MW % Purity High MW Species % Purity Low MW Species % Purity
0 0 0
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Method
Laser passed through container headspace Laser frequency tuned to match internal
absorption frequency of target molecule Absorption is proportional to pressure Amplitude is proportional to concentration
Linearity validation
20%
Measured Oxygen Concentration (%)
20
0 .2 0 .0 -0 .2 -0 .4 -0 .6 -0 .8 -1 .0 -1 .2 -1 .4 -1 .6
13% 8% 4% 2% 1% 0%
W a ve le n g th (a rb itra ry u n its )
15
10
10
15
20
Specifications
Headspace analysis O2 inert gas environment H2O dry product Vacuum < ~500 mbar absolute Non-destructive, rapid (<1 s)
Applications
Glass or transparent plastic packages Vials, ampoules, syringes On-line or off-line systems
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0 0.5 1 2 4 8
0 <1 1 3 6 13
0 4 8 17 36 81
Initial oxygen partial pressure = 0 Torr Hole path length assumed to be 0.1 mm (Courtesy of Lighthouse Instruments, Inc., Charlottesville, VA)
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Initial headspace pressure = 0 Torr Viscous flow kinetics assumed hole path length 1.5 mm air viscosity 1.8 x 10-7 Pas
(Courtesy of Lighthouse Instruments, Inc., Charlottesville, VA)
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SUMMARY
Package integrity related recalls continue to plague industry Current leak testing and package development practices are ineffective in preventing major recalls Commonly used dye ingress tests for CCIT are not considered best practices
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SUMMARY
Best practice leak detection methods meet validation criteria of sensitivity and reliability Validation studies require appropriate positive and negative control test samples CCIT validation studies must reflect specific instruments, methods, packages, and products
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SUMMARY
Best practice leak test methods are supported by data in peer-reviewed publications Best practice methods examples include
Vacuum decay High voltage leak detection Laser-based Headspace Detection
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Thank you
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