Container Closure
Integrity Testing for
Parenteral Containers
PDA: A Global
Association
Author: Marco Renggli, WILCO AG
My first Leak Detection experience
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Worst case?
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WILCO AG
More than just Leak Detection
• Headquarter and manufacturing site in Switzerland
• Founded 1971 – long experience
• Belongs to
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Agenda
1. Benefit of CCI
2. Definition of a Leak
3. Which Testing Method is used for which Product?
– Examples with liquid and lyo filled vials, syringes and ampoules.
4. Comparison of some Testing Methods
– HSA, Pressure/Vacuum Decay and HVLD
5. Decision of the most feasible Testing Method
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1. Benefit of CCI
• Container and closure system integrity must provide
an integral barrier that protects drug product stability
throughout its entire shelf life.
• CCI tester is not able to ensure product sterility at the point of testing.
Product sterility has to be provided throughout the whole production
process.
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2. Definition of a Leak
Leak Tightness requirements and
equivalent Leakrate
General definition
Water tightness
Vapor tight
Bacterial tight
Gasoline/oil tight
Virus tight
Gas tight
Technical tight
Qualifiable Leakrate
[mbar.l.s-1]
10-2
10-3
10-4
10-5
10-6
10-7
10-10
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3. Which Testing Method is used
for which Product?
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Inline CCIT Methods
water bas ed l i qui ds
vi al s
s yri nge s
Ye s
No
No
TDLAS/HSA
LFC
(frequency
modula ted
s pectros copy)
Ye s
Ye s
Yes (under N 2
atmo sphere)
No
Ye s
Yes (under N 2
atmo sphere)
Ye s
Ye s
Ye s
BFS conta i ne rs
No
Ye s
No
Ye s
Yes (under N 2
atmo sphere)
i nfus i on ba gs
No
Ye s ?
No
Ye s ?
No
vi al s
s yri nge s
a mpoul e s
General Obj ects
Ye s
PD/VD combination
Ye s
MDI /Ca ns
Powders and
Lyophi l i s ates
Vacuum
Decay
Yes (under N 2
atmo sphere)
a mpoul e s
Oi l bas ed l i qui ds
Pressure
Decay
No
Ye s
No
High Voltage
Yes (co nductive liquid
and partial co ntainer
o nly)
Yes (co nductive liquid
and partial co ntainer
o nly)
Yes (co nductive liquid
and partial co ntainer
o nly)
Yes (co nductive liquid
and partial co ntainer
o nly)
Mass Spectrometry
3µm IR-SpecForce
troscopy
Detection
No
No
No
No
No
No
No
No
No
No
No
Ye s
No
No
No
Ye s
Yes (LP G o r similar
as pro pellant)
No
No
No
n/a
Yes (LP G o r similar as
pro pellant)
Ye s
Ye s
Ye s
No
Yes (under N 2
atmo sphere)
n/a
No
No
No
No
No
No
No
Yes (under N 2
atmo sphere)
n/a
No
No
No
No
Yes (under N 2
atmo sphere)
n/a
No
No
No
Ye s
Ye s
Ye s
BFS conta i ne rs
No
Ye s
No
No
Yes (under N 2
atmo sphere)
n/a
No
No
Ye s
MDI /Ca ns
No
Ye s
No
No
No
n/a
Yes (LP G o r similar as
pro pellant)
Yes (LP G o r similar
as pro pellant)
No
No
Yes (vacuum o r N 2
atmo sphere)
n/a
n/a
n/a
No
vi a l s
No
Ye s
No
s yri nge s
No
Ye s
No
No
Yes (vacuum o r N 2
atmo sphere)
n/a
n/a
n/a
No
a mpoul e s
Ye s
Ye s
Ye s
No
Yes (vacuum o r N 2
atmo sphere)
n/a
n/a
n/a
No
MDI /Ca ns
No
Ye s
No
No
No
n/a
Yes (LP G o r similar as
pro pellant)
Yes (LP G o r similar
as pro pellant)
No
No
Yes (under N 2
atmo sphere)
n/a
n/a
n/a
Ye s
No
Yes (under N 2
atmo sphere)
n/a
n/a
n/a
Ye s
bl i s ters
pouche s
No
No
Ye s
Ye s
No
No
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Example I: Ampoules
• Pressure Decay testing method
– One-Piece-Container
– Liquid or Lyo filled
– In-line at high capacity
• HSA / TDLAS
(Head Space gas Analysis / Tunable Diode
Laser Absorption Spectroscopy)
• High Voltage Leak Detection
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Pressure Decay Principle
Valve
Pressure
source
Pressure
gauge
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Example III: Lyo Vial
• HSA / TDLAS
– In-line at high capacity
– Head space is needed
• Vacuum Decay testing method
• Further inspection: NIR (Near Infrared) for residual moisture control
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Machine II: P/V/HAS/NIR
for lyo/liquid Vials
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Example II: Liquid Filled Vial
• High Vacuum testing method
– High sensitivity
– In-line at high capacity
– No head space needed
• HSA / TDLAS
• High Voltage Leak Detection
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LFC Functional Principle
High Vacuum (Liquid Filled Container)
Valve
Vacuum
pump
Pressure
gauge
Optimized sensor design for
highest sensitivity in the range of
0.5 - 5 mbar or 0.375 - 3.75 torr
absolute pressure
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LFC for Prefilled Syringes
Floating Pin
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Machine I: LFC for PFS
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4. Comparison of some Testing
Methods
Leak Tightness requirements and equivalent Leakrate
Theoretical indications
Methods
Flowrates in
mbar.l.s-1
Lack Ø in µm
(approx.)
General definition
Pressure Decay
Vacuum Decay
10-2
4 µm
Water tightness
Force Sensor
10-3
2 µm
Vapor tight
LFC
10-4
1 µm
Bacterial tight
TDLAS / HSA
10-6
0,1 µm
Virus tight
Mass Spectroscopy
IR -Spectroscopy
10-6
0,1 µm
Virus tight
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Advantages and Disadvantages
CCI Testing
Advantages
To consider
Vacuum/Pressure - Quantitative leak size
Decay
determination feasible
- High sensitivity (High
Vacuum
- Products may interfere
defect detection
High Voltage
Leak Detection
- Testing under
atmospheric pressure
- Conductive liquid fills
required
- May cause drug
products degradation
HSA - Head
Space gas
Analysis
(TDLAS)
- High sensitivity
- Quantitative leak size
determination feasible
- May detect past
transient CCI failures
- Modified atmosphere
in packaging required
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Comparison: LFC vs. HVLD
Advantage LFC (high vacuum testing method for Liquid Filled Container)
• The entire product is tested
• Leaks are detected regardless whether liquid or air is behind the leak
• No ozone will be generated, either inside or outside the container
• No product damage (see Hospira report)
• No limitation on min. or max. product sizes
• Electrical conductivity of the liquid has no influence
• Exact information in terms of detected leak is given in real time
• Automatic reference adjustment, keeps system always under constant
test sensitivity
• Validation of the entire system is possible
Additional things to consider when using LFC method:
• The product has to be dry on the outside
• If the liquid is high in viscosity (oil-based) it may not vaporize
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5. Decision of the most feasible
Testing Method
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Lyo
products
Gas Overlay
No Gas Overlay
Vacuum
Pressure
HSA
Vials
Pouches
Ampoules
Vials (limited)
Ampoules
Vials
Pouches
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Liquid
products
No Gas Overlay
Gas Overlay
Water Based
Conductive
HVLD
Ampoules
BFS
Vials (limited)
Oil Based
Non-Conductive
High Vacuum
BFS
Syringes
Vials
Pouches
(Ampoules)
Vacuum
Pressure
HSA
Vials (limited)
Pouches
Ampoules
Vials (limited)
Ampoules
BFS
Syringes
Vials
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Summary –Wrap up
• CCI maintains the integrity of the product during its shelf life
• The testing method selection depends on many factors and
There is more than one solution for CCI testing
• CCI testing has to be considered at the initial planning stage
 USP 1207
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Contact Information
Please contact us
Tel.: +41 (0)56 6184343
E-mail: [email protected]
www.wilco.com
We would be pleased to give you a demonstration of
our machines
SWISS PRECISION
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Publikationen 2015