Container Closure Integrity Testing - … · Vacuum decay Corona discharge testing Probabilistic...

1 | P HA RMA & B IOT E CH | P ROT E IN T HE RA P E UT ICS MA NUFA CT URING | MAY 20 – 22 , 2015

Container Closure Integrity Testing Practical Aspects and Approaches in the Pharmaceutical IndustryIndustry considerations related to draft USP <1207>

Hanns-Christian Mahler

AAPS NBC

Boston | 16.05.2016

Pharma&Biotech


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.


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).


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.

(Some) Regulatory requirements


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.

Challenges related to CCI, pCCI and CCIT


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

Primary Goal of CCI Industry Expert Paper


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


USP <1207> Package Integrity Test Method Leak Detection Index

Detectable Leaks Expressed in Two Different

Units of Measure

Limit of Detection

Index Classification

Air Leakage

Ratea (stdcm3/s) Orifice Leak Sizeb (µm)

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

?

http://www.usppf.com/pf/pub/data/v405/CHA_IPR_405_c1207_1.html#CHA_IPR_405_c1207_1-tb1-f1

http://www.usppf.com/pf/pub/data/v405/CHA_IPR_405_c1207_1.html#CHA_IPR_405_c1207_1-tb1-f2


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

When to test / evaluate CCI ?

10 | P HA RMA & B IOT E CH | P ROT E IN T HE RA P E UT ICS MA NUFA CT URIN G | MAY 20 – 22 , 2015

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)

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


Comparison CCIT methodsWuchner et al., PDA J Pharm Sci Technol, in submission

Technique Measuring Principle Advantages (literature, instrument

manufacturer)

Disadvantages (literature,

instrument manufacturer)

Author Experience and Area of Application

High voltage leak

detection

(electrical

conductivity and

capacitance

Deterministic. Based on a quantitative electrical conductance measurements. The

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

pass/fail threshold.

Non-destructive

Feasible for 100% online testing

Rapid

No sample preparation required

Accuracy not dependent on operator skill

Testing performed under normal atmospheric pressure

Pass/fail result, no quantitative result

Product must be more conductive than the package

Potential for damage to the product (e.g. protein degradation)

The formulation must not be flammable

Ozone generation

Special fixtures are required for a specific CCS

Electrodes must be within a certain distance of leak for detection

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

High throughput on commercial production line

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 prolongedstorage

Risk that conductivity of the drug product is not sufficient to detect a defective syringe

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

Limited applicability for cracks in the vial head region under the crimp cap given lack of product liquid contact

Laser-based

headspace

analysis (17-18)

Deterministic. Assessment of package headspace via laser-based analysis techniques

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.

A near-infrared diode laser light is passed through the gas headspace region of the

sealed package. Light absorption, measured using frequency-modulated spectroscopy,

is indicative of gas concentration and pressure.

Non-destructive

Quantitative


Rapid measurement

The container must be transparent

Requires modified atmosphere in the headspace

Requires a certain minimum volume of headspace with a certain size window for

detection

Will take an extended period of time to detect small leak size the longer

Change parts need to cover different container sizes and types

Could take weeks of gas exchange to detect micron-sized leaks

Easy to use

Can be used to evaluate transient leaks (e.g. for products stored under cryogenic conditions)

Risk of false results, particularly during stability testing due to gas permeation or absorption of the tracer gas into the l iquid product

phase

Large leaks may not be detectable (e.g. for studies under cryogenic conditions) because of fast equilibration with ambient ai r

Difficult to discriminate between different leak sizes

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

Helium leak test

(14, 19)

Deterministic. Helium-filled or flushed samples are placed in a test chamber, where a

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,

enter the test system, and be detected by an analyzer cell. The stream of helium ions

hitting the analyzer cell target is proportional to the partial pressure inside a sample.

Quantitative

Short measurement time needed

Wide range of CCS sizes can be analyzed

A specific leak rate can be calculated

Accurate and reproducible results.

Very sensitive (if flow rate is determined by a mass spectrometer)

American Standard for Materials Testing (ASTM) available

Destructive

Low throughput

Off line use only


Reproducible and easy to use once tooling has been qualified

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)

Mass extraction,

mass flow (20-21)

Deterministic. A vacuum is drawn on a sample enclosed in a chamber. Once a vacuum is

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

the amount of flow escaping from leaks in the sample under test.

Non-destructive

Quantitative

100% testing feasible

Flexible, can be used on liquid and lyophilized samples and plastic

bottles/intravenous (IV) bags

Sensitive

Product clogging could lead to incorrect results Detection sensitivity to two micronmeter leak size is possible

It has long cycle times with large packages

Good repeatability for testing the same packages multiple times

Labeled packaging can induce false positives due to off-gassing; testing unlabeled samples mitigates this potential issue

Pressure decay

(20, 23)

Deterministic. A test package is placed into a custom-designed test chamber that is

subsequently exposed to overpressure. Sensitive pressure transducers monitor changes

in chamber pressure. A pressure drop indicates a leak.

Non-destructive


ASTM method available

Typically only a pass/fail result


Less sensitive than vacuum decay test

High throughput on commercial production line

Vacuum decay (14,

20, 24-25)

Deterministic. A test package is placed into a custom-designed test chamber that is

subsequently exposed to vacuum. Sensitive pressure transducers monitor changes in

chamber pressure. A pressure increase indicates a leak.

Non-destructive


Rapid

No time lapse between manufacture and testing necessary


Can be used on liquid and lyophilized samples

Can be used on colored CCS’s and labeled samples

Expensive equipment which requires specific instrumentation / tailored test

chambers for each CCS


Vacuum chamber preparation is critical (humidity can impact on measurement

results)

Versatile and can be used on primary and secondary packaging in support of development, manufacturing and stability testing

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

packaging

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)

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 small

leaks or single breach or gap in CCS can be made

Corona discharge

testing (16)

Deterministic. A high voltage frequency electrode is applied to the outside of the sample.

Gas molecules in the sample’s headspace are ionized followed by a Corona discharge

(glow) measured as a current/ discharge pattern.

Non-destructive

100% testing feasible

Rapid

No sample preparation required

Accuracy is not dependent on operators skill

Testing is conducted under ambient atmospheric pressure

Headspace required

CCS has to be closed under a vacuum

There is a threshold for minimum detectable vacuum level

Potential ozone creation, thus potential for damage to the product

Does not work for a CCS closed under atmospheric pressure

Reliable detectable vacuum range is limited

Currently not widely used and a lack of published data specific to CCIT

Bubble emission

(26)

Probabilistic. The test package is submerged into an immersion fluid and inflated by

applying a defined vacuum or an overpressure. Evidence of bubble emission through the

package is considered a failure.

Widely used for decades


Inexpensive

Convenient and easy to use

Good for flexible packaging

Leak location can be confirmed

Destructive


100% testing is not possible

Easy to train the operator and perform the test. However, the results can depend on operator technique and can take several

minutes per sample.

Limit of detection (LOD) may be too high to assess microbial contamination risk.

Dye ingress (liquid

tracer test) (14, 27-

30)

Probabilistic. In its most common form, a package is placed in a bath of water with a dye

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

released from the test chamber. If the package cavity leaks air the package cavity will

have a reduced pressure drawing dye into the package cavity. Subsequent exposure to

increased pressure can enhance dye penetration if leak is present. An operator (or

instrument) will then inspect the package for any degree of coloration, i.e. dye ingress.


ASTM and ISO methods available (31-35)

Industry and regulatory familiarity

Basic and efficient

Flexible, can be used for several different CCS’s (types and size and products)

in same run

The leak location can be specified

The leak can be in the liquid phase


Destructive


The test samples need to be transparent, for visual assessment

In larger volume products ingress of small amounts of tracer liquid may be more

challenging to detect

Detection is probabilistic particularly for small size defects

Versatile and can be used on primary and secondary packaging in support of development, manufacturing and stability testing

Detects directly relevant leaks of concern

Different dyes can be used to tailor the method

Improved sensitivity when optimized vacuum/pressure cycles are used. LOD varies depending on the leak size, materials, dye

concentration and challenge conditions

The tracer liquid must be miscible and not chemically reactive with the product

Correlation to microbial ingress can be established using the same challenge conditions

Has been seen to work well for liquids but depending on the dye it may not be suitable for lyophilized products

Microbial

immersion or

aerosol challenge

(mCCI) (20, 27, 31)

Probabilistic. The sample is filled with sterile nutritive media, then the outside of the

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

storage time are classed as a failure.


Industry and regulatory familiarity

Readily incorporated into media fill runs

Direct assessment of relevant property (i.e. maintenance of integrity with

respect to microbial contamination)

Destructive



Can take weeks

Labor intensive

Media filled CCS only

Potential for false positives and false negatives; the level of detection is partly

related to operator technique

Detection is probabilistic for small size defects

No harmonization on media and organisms and method specifics

Can be used for offline testing

The LOD varies with leak size, materials, organisms, media and challenge conditions

Historically used to establish a critical leak (rate or size)

The submersion method is more common and easier to set up and more reproducible than the aerosol method

Long term checks over a period of weeks without using vacuum or overpressure can be more representative of actual storage

conditions

Short term checks over a period of hours with applying vacuum and/or overpressure can be more representative of transport

conditions and reduces test time


CCIT methods – Some Selection CriteriaWuchner 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)


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

Artifical Leaks


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

Leak Type Advantages Disadvantages Author Experience Micro-pipettes,

0.4 to 5µm (e.g.

glass)

Easy sample preparation Fragile and broken tips may not be easily

detected

Difficult to determine “hole size”

Difficult to handle

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

Laser-drilled

holes

Nominal leak size >1µm orifice size

Better resembles natural defects in

glass (cracks) and polymer

(pinholes)

State of the art laser drilling

processes result in defined holes

(e.g. holes are drilled with the cold

ablation process, showing fewer

cracked pathways). This new

technique is, however, more

expensive.

Cost

The size of laser-drilled void needs to be

calibrated and represent a defined path

Small holes can clog easily, e.g. silicone oil

or highly viscous liquids, or even lengthen

Holes can increase size in glass materials

from a crack under tension or when

exposed to large temperature changes in a

short period of time

Can get wide a variability in hole size. May

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)

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

Capillaries (e.g.

Fused silica

capillaries)

Robust

Easy preparation directly at the

testing location

Possibility to prepare positive

controls in a specific packaging

format and for multiple products

(e.g. syringes and lyophilized vial

products)

Can be prepared in a flexible way

(e.g. may contact liquid and

headspace)

The length of the microtube defects is

usually longer than that of typical real life

defects, which may affect the flow pattern

Typically nominal diameters >2µm

available and high uncertainty with respect

to the actual diameter

In regard to flow rate, capillary diameter

and hole diameter are not comparable

Care should be taken if glue is present as

blockage can occur

Dye ingress works well with liquid-filled products

but not so well with lyophilized products

Injection needles are not an adequate substitute

because inner diameter is too wide

Micron wires (e.g.

uncoated copper)

Low cost

Robust

Handling of the micron wires can be

difficult and the size of the void needs to

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

(37)

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


Justification is required for the rationale to set acceptance

criteria based on a predictable leak rate and microbial

contamination

Reference and Acceptance Criteria setting of pCCITWuchner et al., PDA J Pharm Sci Technol, in submission

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.


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


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.


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, IngeborgKraemer 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

Acknowledgments


Lonza - Drug Product ServicesSupporting the Development & Manufacture of Your Parenteral Drug Product

Customer Patient

Formulation Development

Analytics & QC

Drug Product

Primary Packaging

Drug Product

Manufacturing

& Processing

Container Closure Integrity

Seal Quality

Extractables/

Leachables

Particles Identification

& Characterization

URL www.lonza.com/DrugProduct | Email [email protected]

http://www.lonza.com/DrugProduct

mailto:[email protected]

Container Closure Integrity Testing - … · Vacuum decay Corona discharge testing Probabilistic...

Documents

Transcript of Container Closure Integrity Testing - … · Vacuum decay Corona discharge testing Probabilistic...