Pharma&Biotech

Container Closure Integrity Testing

Practical Aspects and Approaches in the Pharmaceutical Industry
Industry considerations related to draft USP <1207>

Hanns-Christian Mahler
AAPS NBC
Boston | 16.05.2016
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 Forward-Looking Statements

Certain matters discussed in this presentation may constitute forward-looking

statements. These statements are based on current expectations and estimates
of Lonza Group Ltd, although Lonza Group Ltd can give no assurance that these
expectations and estimates will be achieved. Investors are cautioned that all
forward-looking statements involve risks and uncertainty and are qualified in their
entirety. The actual results may differ materially in the future from the forward-
looking statements included in this presentation due to various factors.
Furthermore, except as otherwise required by law, Lonza Group Ltd disclaims any
intention or obligation to update the statements contained in this presentation.

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Container Closure Integrity of Parenteral Products

All products labeled as sterile are required to be

free of microbial contamination throughout their
shelf life (obligatory CQA).

Sterility testing alone does not provide assurance

of product sterility.

Container closure integrity (CCI) addresses the

maintenance of integrity to prevent
microbiological ingress in sterile product
packaging until the time of use (product opening).

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 (Some) Regulatory requirements
 USP <1207>, Package Integrity Evaluation - Sterile Products. First supplement to USP 39-NF34.
 ICH Harmonised Triplicate Guideline Pharmaceutical Development Q8(R2). Current Step 4 version.
 ICH Q 5 C: Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological
Products. Part 5.
 Annex 1, EU-GMP
 Section 11. Media Fill test. Japanese Pharmacopoeia, JPXV.
 Section 5.1.1. Methods of Preparation of Sterile Products. European Pharmacopoeia, 8th Edition.
 USP<671> Containers – Performance Testing.
 FDA Guidance for Industry. Container Closure Systems for Packaging Human Drugs and Biologics,
(Chemistry, Manufacturing, and Controls Documentation). 1999.
 FDA Guidance for Industry, Container and Closure System Integrity Testing in Lieu of Sterility Testing
as a Component of the Stability Protocol for Sterile Products. 2008.
 Commision Directive 2003/94/EC. Official Journal of the European Union 2003.
 Directive 2001/83/EC. Official Journal of the European Union 2001.
 Directive 93/42/EEC. Official Journal of the European Union 1993.
 World Health Organization, Annex 9: Guidelines on packaging for pharmaceutical products. WHO
Technical Report Series 2002, (902), 121-122.

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 Challenges related to CCI, pCCI and CCIT
Problem statements

 There is currently no universally accepted test method nor gold

standard for conducting CCIT.
 Worldwide and local regulatory requirements offer no clear
distinction as to what is required for microbiological quality (sterility)
shall be maintained until the end of product shelf life.
 Artificial leaks do not necessarily simulate actual defects due to, for
example, irregular shapes and pathways in a CCS. There is also
high variability depending on the method used to create such holes.
Artificial leaks also cannot be easily related to a leak size.
 There is a need to correlate microbial contamination and the
physical CCI (pCCI) test method.
 Different CCIT methods can serve the same purpose when
appropriately validated.
 Local regulations may differ and should be considered as well as
experience within an organization.

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 Primary Goal of CCI Industry Expert Paper
Main Purpose of the paper

 Address common understanding of the application of

container closure integrity testing (CCIT)
 Raise awareness throughout the industry of the
complexity of topics when evaluating leaks in
container closure systems (CCS)
 Reflect the experiences of the contributing companies
and is not regarded to be exhaustive of the industry

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The new draft USP <1207>
1207.1 Package Integrity and Test Method Selection.
 Package integrity and testing during product life cycle
 Package development and validation
 Product manufacturing
 Commercial Product stability
 Test method selection criteria, incl
 Package Integrity Test Method Leak & Leak Detection Index
 Probabilistic vs Determinstic Methods
 Test instrument qualification, method development and method validation
1207.2 Package Integrity Leak Test Technologies.
 Deterministic and probabilistic method descriptions
1207.3 Package Seal Quality Test Methods
 Closure application and removal torque
 Package burst test
 Package seal strength (Peel test)
 Residual seal force
 Airborne ultrasound
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USP <1207> Package Integrity Test Method Leak Detection Index

Detectable Leaks Expressed in Two Different

Units of Measure

Limit of Detection Air Leakage

Index Classification Rate (stdcm3/s)
a Orifice Leak Size (µm)
b

1 <10 6 <0.1
2 10 6 to 10 4 0.1 to 1
3 6 × 10 4 to 4 × 10 3 2 to 5
4 5.0 × 10 3 to 1.6 × 10 2 6 to 10
5 0.017 to 0.360 11 to 50
6 >0.36 >50

?
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 When to test / evaluate CCI ?

Container Closure Integrity needs to be ensured and

evaluated across a product lifecycle

 Container closure system (CCS) qualification (prior first human use):

 Evaluation and transportation and storage conditions

 During drug product manufacturing / processing characterization and

validation

 Routine drug product manufacture

 For Quality Control purposes (release and stability)

… from clinical to commercial

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 CCIT methods – determinstic vs probabilistic
according USP <1207> and CCIT method examples

Deterministic method: A method in which the leakage event being detected, or

measured, is based on phenomena that follow a predictable chain of events. In
addition, the measurement of leak detection is based on physicochemical
technologies that are readily controlled and monitored, yielding objective
quantitative data.
 High voltage leak detection (electrical conductivity and capacitance
 Laser-based headspace analysis
 Helium leak test
 Mass extraction, mass flow
 Pressure decay
 Vacuum decay
 Corona discharge testing
Probabilistic method: A method which is the converse of a deterministic leak test
method, being stochastic in nature. Probabilistic tests rely on a series of sequential
and/or simultaneous events, each associated with random outcomes described by
probability distributions. Thus, the findings are associated with uncertainties that
necessitate sufficiently large sample sizes and rigorous test-condition controls to
obtain meaningful results.
 Dye ingress (liquid tracer test)
 Bubble emission
 Microbial immersion or aerosol challenge (mCCI)
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 Comparison CCIT methods
Wuchner et al., PDA J Pharm Sci Technol, in submission

Technique Measuring Principle Advantages (literature, instrument Disadvantages (literature, Author Experience and Area of Application
manufacturer) instrument manufacturer)
Deterministic. Based on a quantitative electrical conductance measurements. The  Non-destructive  Pass/fail result, no quantitative result  High throughput on commercial production line
High voltage leak presence of a leak path in the proximity of electrically conductive liquid results in a drop in
test sample electrical resistance, shown as a spike in current above a predetermined


Feasible for 100% online testing
Rapid


Product must be more conductive than the package
Potential for damage to the product (e.g. protein degradation)


Need to assess product quality after exposure to voltage
Limitations for use in long term stability testing due to clogging (drying out) of liquid residues in the voids during prolonged storage
 No sample preparation required  The formulation must not be flammable  Risk that conductivity of the drug product is not sufficient to detect a defective syringe
pass/fail threshold.
detection 

Accuracy not dependent on operator skill
Testing performed under normal atmospheric pressure


Ozone generation
Special fixtures are required for a specific CCS


A 100% online module can be integrated with the automated visual inspection
Has limited sensitivity in 100% online testing because only larger leak sizes, i.e. visually leaking cracks, are detected
 Electrodes must be within a certain distance of leak for detection  Limited applicability for cracks in the vial head region under the crimp cap given lack of product liquid contact
(electrical 

Product liquid needs to be in contact or close to the leak
Product clogging could lead to incorrect results
 Does not work for lyophilized products

conductivity and
capacitance
Deterministic. Assessment of package headspace via laser-based analysis techniques  Non-destructive  The container must be transparent  Could take weeks of gas exchange to detect micron-sized leaks
Laser-based provides a quantitative, non-destructive measure of oxygen, nitrogen, carbon dioxide,
water vapor, or internal pressure in a non-porous, rigid or non-rigid package’s headspace.


Quantitative
Feasible for 100% online testing


Requires modified atmosphere in the headspace
Requires a certain minimum volume of headspace with a certain size window for


Easy to use
Can be used to evaluate transient leaks (e.g. for products stored under cryogenic conditions)
 Rapid measurement detection  Risk of false results, particularly during stability testing due to gas permeation or absorption of the tracer gas into the l iquid product
A near-infrared diode laser light is passed through the gas headspace region of the
headspace sealed package. Light absorption, measured using frequency-modulated spectroscopy,


Will take an extended period of time to detect small leak size the longer
Change parts need to cover different container sizes and types 
phase
Large leaks may not be detectable (e.g. for studies under cryogenic conditions) because of fast equilibration with ambient ai r
is indicative of gas concentration and pressure.  Difficult to discriminate between different leak sizes
analysis (17-18) 

Difficulties resp inability in detecting leaks located in the liquid solution area, thus, limited applicability for filled syringes or cartridges
Potential for clogging in lyophilisate products
 Partial pressure is temperature-dependent

Deterministic. Helium-filled or flushed samples are placed in a test chamber, where a  Quantitative  Destructive 

Reproducible and easy to use once tooling has been qualified

Helium leak test vacuum is created by the instrument’s internal pumps. Fixtures may be required to
isolate particular package areas of interest. Leaking samples allow helium to escape,


Short measurement time needed
Wide range of CCS sizes can be analyzed


Low throughput
Off line use only


Cannot be performed on intact product containing packages unless under artificial helium atmosphere (e.g. via bombing), i.e. destructive test
Detection sensitivity to 2 micrometers and possibly below considerable
Can be used for testing samples for frozen drug products/at low temperatures (20-22)

 A specific leak rate can be calculated  Product clogging could lead to incorrect results
enter the test system, and be detected by an analyzer cell. The stream of helium ions
(14, 19) hitting the analyzer cell target is proportional to the partial pressure inside a sample.


Accurate and reproducible results.
Very sensitive (if flow rate is determined by a mass spectrometer)
 American Standard for Materials Testing (ASTM) available

Deterministic. A vacuum is drawn on a sample enclosed in a chamber. Once a vacuum is  Non-destructive  Product clogging could lead to incorrect results  Detection sensitivity to two micronmeter leak size is possible
Mass extraction, established, the instrument monitors the amount of airflow required to sustain a specific 
vacuum level. The amount of flow required to keep the vacuum steady is proportional to 
Quantitative
100% testing feasible


It has long cycle times with large packages
Good repeatability for testing the same packages multiple times
 Flexible, can be used on liquid and lyophilized samples and plastic  Labeled packaging can induce false positives due to off-gassing; testing unlabeled samples mitigates this potential issue
the amount of flow escaping from leaks in the sample under test.
mass flow (20-21) 
bottles/intravenous (IV) bags
Sensitive

Deterministic. A test package is placed into a custom-designed test chamber that is  Non-destructive  Typically only a pass/fail result  Less sensitive than vacuum decay test
Pressure decay subsequently exposed to overpressure. Sensitive pressure transducers monitor changes 
in chamber pressure. A pressure drop indicates a leak. 
Feasible for 100% online testing
ASTM method available
 Product clogging could lead to incorrect results  High throughput on commercial production line

(20, 23)
Deterministic. A test package is placed into a custom-designed test chamber that is  Non-destructive  Expensive equipment which requires specific instrumentation / tailored test  Versatile and can be used on primary and secondary packaging in support of development, manufacturing and stability testing
Vacuum decay (14, subsequently exposed to vacuum. Sensitive pressure transducers monitor changes in
chamber pressure. A pressure increase indicates a leak.


Feasible for 100% online testing
Rapid 
chambers for each CCS
Product clogging could lead to incorrect results


Suitable for liquid and lyophilized products
Can be used for device testing and for products with labels; however, test sensitivity is reduced compared to unlabeled primary
 No time lapse between manufacture and testing necessary  Vacuum chamber preparation is critical (humidity can impact on measurement packaging
20, 24-25) 

ASTM method available
Can be used on liquid and lyophilized samples
results)  Limitations for on-line use, generation of false positive results (e.g. due to potential for air entrapment within a crimped cap or
humidity fluctuations)
 Can be used on colored CCS’s and labeled samples  Development studies have shown equivalent sensitivity for lyophilized product and liquid filled syringes and vials
 Rapid clogging observed for positive controls which contained laser drilled holes in contact with the liquid product (viscosi ty
limitations) or clogging by proteins or silicone oil in pre-filled syringes
 Magnitude of pressure change can be correlated with size of leak or leakage rate, however, no distinction between multiple sm all
leaks or single breach or gap in CCS can be made

Deterministic. A high voltage frequency electrode is applied to the outside of the sample.  Non-destructive  Headspace required  Does not work for a CCS closed under atmospheric pressure
Corona discharge Gas molecules in the sample’s headspace are ionized followed by a Corona discharge
(glow) measured as a current/ discharge pattern.


100% testing feasible
Rapid


CCS has to be closed under a vacuum
There is a threshold for minimum detectable vacuum level


Reliable detectable vacuum range is limited
Currently not widely used and a lack of published data specific to CCIT
 No sample preparation required  Potential ozone creation, thus potential for damage to the product
testing (16) 

Accuracy is not dependent on operators skill
Testing is conducted under ambient atmospheric pressure
Probabilistic. The test package is submerged into an immersion fluid and inflated by  Widely used for decades  Destructive  Easy to train the operator and perform the test. However, the results can depend on operator technique and can take several
Bubble emission applying a defined vacuum or an overpressure. Evidence of bubble emission through the 
package is considered a failure. 
ASTM method available
Inexpensive


Pass/fail result, no quantitative result
100% testing is not possible 
minutes per sample.
Limit of detection (LOD) may be too high to assess microbial contamination risk.
 Convenient and easy to use
(26) 

Good for flexible packaging
Leak location can be confirmed
Probabilistic. In its most common form, a package is placed in a bath of water with a dye  Widely used for decades  Pass/fail result, no quantitative result  Versatile and can be used on primary and secondary packaging in support of development, manufacturing and stability testing
Dye ingress (liquid and perhaps surfactant within a test chamber and a set vacuum is drawn on the
package. The method attempts to draw air out of the package cavity. The vacuum is then 
 ASTM and ISO methods available (31-35)
Industry and regulatory familiarity


Destructive
100% testing is not possible


Detects directly relevant leaks of concern
Different dyes can be used to tailor the method
 Basic and efficient  The test samples need to be transparent, for visual assessment  Improved sensitivity when optimized vacuum/pressure cycles are used. LOD varies depending on the leak size, materials, dye
released from the test chamber. If the package cavity leaks air the package cavity will
tracer test) (14, 27- have a reduced pressure drawing dye into the package cavity. Subsequent exposure to
 Flexible, can be used for several different CCS’s (types and size and products)
in same run
 In larger volume products ingress of small amounts of tracer liquid may be more
challenging to detect 
concentration and challenge conditions
The tracer liquid must be miscible and not chemically reactive with the product
increased pressure can enhance dye penetration if leak is present. An operator (or  The leak location can be specified  Detection is probabilistic particularly for small size defects  Correlation to microbial ingress can be established using the same challenge conditions
30) instrument) will then inspect the package for any degree of coloration, i.e. dye ingress.  The leak can be in the liquid phase  Has been seen to work well for liquids but depending on the dye it may not be suitable for lyophilized products

Probabilistic. The sample is filled with sterile nutritive media, then the outside of the  Widely used for decades  Destructive  Can be used for offline testing
Microbial container is challenged with an actively growing motile micro-organism in order to assess 
container closure integrity. Any microbes detected in the sample after a defined period of 
Industry and regulatory familiarity
Readily incorporated into media fill runs


Pass/fail result, no quantitative result
100% testing is not possible


The LOD varies with leak size, materials, organisms, media and challenge conditions
Historically used to establish a critical leak (rate or size)
 Direct assessment of relevant property (i.e. maintenance of integrity with  Can take weeks  The submersion method is more common and easier to set up and more reproducible than the aerosol method
storage time are classed as a failure.
immersion or respect to microbial contamination) 

Labor intensive
Media filled CCS only
 Long term checks over a period of weeks without using vacuum or overpressure can be more representative of actual storage
conditions
 Potential for false positives and false negatives; the level of detection is partly  Short term checks over a period of hours with applying vacuum and/or overpressure can be more representative of transport
aerosol challenge 
related to operator technique
Detection is probabilistic for small size defects
conditions and reduces test time

 No harmonization on media and organisms and method specifics

(mCCI) (20, 27, 31)

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 CCIT methods – Some Selection Criteria
Wuchner et al., PDA J Pharm Sci Technol, in submission

 The intended purpose, e.g. CCS development and qualification,

manufacturing process control or validation, or release or stability testing
 Prior knowledge of the CCS, e.g. initial product development with a CCS
vs. further development of a CCS for a new product
 The CCS format, e.g. vial, syringe, drug/device combination product, IV bag
 The CCS material, e.g. flexible, glass, polymer
 The type of product, e.g. liquid vs. lyophilisate, small vs. large molecule,
water-based formulation vs. solvent or oily, conductivity, viscosity, ambient
pressure or vacuum/overpressure
 Test duration
 The required sensitivity
 The type and availability of samples with artificial leaks
 The sample size required for a specific study
 Teed for sample preparation and potential risks associated with the
sample preparation (e.g. label removal, vials to be emptied and cleaned)
 Other (eg in-line, on-line, off-line, test efficacy, costs, test output)

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 Artifical Leaks

Unit container with artificial leaks are required in order to

assess a CCIT method capability to detect a leak and also act
as positive controls

 Different methods for artificial leaks considerable, e.g.

• laser drilling into the body of the container
• laser drilling into a metal plate or tubing that is integrated to a CCS
• micron wires inserted at the interface between the closure and
container
• micropipettes (glass) inserted into the stopper or glued into an artificial
hole of the container
• capillaries (fused silica, nickel, glass) inserted into the stopper or glued
into an artificial hole of the container

 No gold standard
 Each approach has advantages and disadvantages
 It cannot be assumed that the Artifical Leaks are somewhat
representive to actual product defects

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 Experience with Artificial Leaks
Wuchner et al., PDA J Pharm Sci Technol, in submission

Leak Type Advantages Disadvantages Author Experience

 Easy sample preparation  Fragile and broken tips may not be easily
Micro-pipettes, detected
0.4 to 5µm (e.g.  Difficult to determine “hole size”
 Difficult to handle
glass)
 Nominal leak size >1µm orifice size  Cost
Laser-drilled  Better resembles natural defects in  The size of laser-drilled void needs to be
holes glass (cracks) and polymer calibrated and represent a defined path
(pinholes)  Small holes can clog easily, e.g. silicone oil
 State of the art laser drilling or highly viscous liquids, or even lengthen
processes result in defined holes  Holes can increase size in glass materials
(e.g. holes are drilled with the cold from a crack under tension or when
ablation process, showing fewer exposed to large temperature changes in a
cracked pathways). This new short period of time
technique is, however, more  Can get wide a variability in hole size. May
expensive. differ according to material and wall
thickness
 Holes can be irregular shape
 Positive controls cannot be prepared
directly on the product (e.g. for stability
testing purposes)
 Robust  The length of the microtube defects is  Dye ingress works well with liquid-filled products
Capillaries (e.g.  Easy preparation directly at the usually longer than that of typical real life
Fused silica testing location defects, which may affect the flow pattern 
 Possibility to prepare positive  Typically nominal diameters >2µm
capillaries) controls in a specific packaging available and high uncertainty with respect
format and for multiple products to the actual diameter
(e.g. syringes and lyophilized vial  In regard to flow rate, capillary diameter
products) and hole diameter are not comparable
 Can be prepared in a flexible way  Care should be taken if glue is present as
(e.g. may contact liquid and blockage can occur
headspace)
 Low cost  Handling of the micron wires can be
Micron wires (e.g.  Robust difficult and the size of the void needs to
uncoated copper) be calibrated and represent an undefined
path
 The holes can close up over time
depending on the relaxation of the
materials (e.g. stopper)
 No direct measurement of hole size exists
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1 4 | P H A R M A & B I O T E C H | P R O T E I N T H E R A P E U T I C S M A N U FA C T U R I N G | (37)
 Too fragile for routine use
 High risk of false sensitivity after preparation of a
positive control
 Complete seal around micropipette is required
 Silicone oil can cause clogging
 Non-negligible risk of alteration of void post
manufacture and/or calibration
 Requires a specialized external supplier with
shipment or prepared and calibrated units
 A small hole (≤ 5 to 10 microns) may not show
product leakage when laser drilled on filled
containers
 Holes typically do not increase significantly over
time due to lab-based controls of temperature
 May re-use positive control samples, but this
must be verified
 Can get wide variability in hole size and may
differ according to material and wall thickness
 Drilling and shipment may not be in a clean
environment, so dirt or particulates could impact
the quality of the holes created
 The service is offered by few companies
but not so well with lyophilized products
Injection needles are not an adequate substitute
because inner diameter is too wide
 Reproducible leak size with defined capping
parameters and wire diameter (37)
 Leak size only defined when measured relative to
a physical phenomenon
 Need to consider actual copper wire diameter and
elastomer behavior for repeatability
 Reference and Acceptance Criteria setting of pCCIT
Wuchner et al., PDA J Pharm Sci Technol, in submission

Justification is required for the rationale to set acceptance

criteria based on a predictable leak rate and microbial
contamination

 Unit container with artificial leaks are required to assess a CCIT

method capability to detect a leak and also act as positive controls
 Different methods for artificial leaks considerable
 mCCIT is one way of supporting the establishment of acceptance
criteria for a pCCIT based on experimental data during initial
evaluation of a CCS (correlation of mCCI and pCCI output data)
 Or establish the acceptance criteria for a pCCIT is to reference
established literature or company-based studies with comparable
CCSs if a suitable justification is provided
 There is no universal way for setting acceptance criteria based on the
probability of microbial ingress
 e.g. some companies declare “positive” when 1% and some when 100% of the
samples show ingress in the study.

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 Example: mCCI and pCCI correlation
Mathaes et al., Impact of Vial Capping on Residual Seal Force and Container Closure Integirty, PDA J, 2016

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 Summary & Conclusions

 Ensuring sterility of a parenteral drug product -to the

end of its shelf-life and prior to any human use- is a
regulatory requirement and warrants product safety.
 For container closure system (CCS) qualification
 During manufacturing
 For Quality Control purposes
 During storage and shipment up to the end of shelf life.
 Current regulatory guidance, which is country specific, provides limited
detail on how to assess CCI.
 USP draft <1207> aims to provide extensive and detailed guidance for
CCI assessments
 CCI industry experts concluded that there is currently no gold standard
for CCI test methods or generation of artificial leaks, flexibility towards
CCI approaches is required.
 Any CCI approach must consider the intended use, product design and phase of
development.
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Acknowledgments
Authors & Contributors from CCI industry discussion group
Klaus Wuchner, Rene Spycher, Johnson and Johnson, Schaffhausen, CH

Helen Brown, Alejandra Nieto, Markus Hemminger, Sascha Dreher, Holger Roehl, Ingeborg
Kraemer Pittrof, F. Hoffmann-LaRoche , Basel, CH & Nathalie Yanze, Genentech, SSF, USA

Franz Schmitting, Abbvie, Ludwigshafen, D

James Mellman, Juergen Kossinna , Matthias Schaar, Novartis, Basel & Stein, CH &Lisa Blackwell,
Alcon, USA

Daniel Wagner, Sanofi, Frankfurt, D

Roman Mathaes, Hanns-Christian Mahler, Lonza, Basel, CH

Jörg Zürcher, Bayer, Wuppertal, D

Pierre Guiswe, Boehringer Ingelheim, Biberach, D

Jacques Maring, CSL Behring, CH

Valeria Delia, Merck Serono, Rome, I

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Lonza - Drug Product Services
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URL www.lonza.com/DrugProduct | Email DrugProduct@lonza.com

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