Leak tests in Parenteral Preparations

Container-Closure Integrity Test (CCIT)

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Objective of this session

At the end of this session you will:• Know why leakage should be avoided in parenteral drugs• Know the basics of leakage testing (Container-Closure

Integrity Test (CCIT))• Be familiar with different technologies and machinery

currently used for leakage testing• Know the criteria for choosing the appropriate leak test• Be familiar with Regulatory aspects and requirements of

these tests.

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Leaks in parenterals: Why are they important?Leaks can be due to incomplete and defective Sealing, Rubber-stoppering and

Crimping, Cracks and Pinholes in packaging.

Leaks can cause loss of product (evaporation, seeping of liquid,…). Leaks and cracks can cause loss of headspace gas leading to product decay. Leaks can cause microbial/physicochemical contamination of the product. Leaks can pose hazards to those handling the product (product contact, breakage

of packaging,…). Particularly in case of parenteral preparations, leaks can cause loss of sterility. Leaks due to cracks, pinholes, incomplete seals,… are all critical defects which can

lead to complaints, recalls and damages to the reputation and finances of a company.

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Leak and Defects in CCs for parenterals are considered Critical DefectsA CRACK IN A GLASS AMPOULE OR GLASS VIAL IS IN FACT A BREACH OF STERILITY.

WHY ARE SOME CCIT VENDORS CLAIMING IT IS NOT NECESSARY TO DETECT A CRACK??

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FDA Recalls due to CCIT Defects and particles in parenterals 1/2

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FDA Recalls due to CCIT Defects and particles in parenterals 2/2

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Leak tests in Product Life Cycle

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Leak tests: Introduction to methodsThere are various methods used for leak detection in different dosage formsSome methods are beyond scope of this presentations (e.g. Aerosols, Flexible containers/bags, Packages of medical devices). The methods are constantly evolving.

The following methods are the ones used mostly for paretnerals: Visual inspection Visual inspection by X-RAY based technology Bubble test Dye test Microbial ingress test Vacuum ionization test

(Corona discharge test) Vacuum and Pressure decay methods Force sensor technology, FS for flexible bags Mass spectrometry, MS Liquid filled container, LFC WILCO method High Voltage Leak Detection (HVLD); High Voltage Spark test

There are also SEAL QUALITY TEST methods which can be further studied (refer to References)

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Deterministic vs. Probabilistic methods 1/3

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Deterministic vs. Probabilistic methods 2/3

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Deterministic vs. Probabilistic methods 3/3

Visual inspection (either with simple inspection, coupled with dye test or with X-rRy), is also considered a Probabilistic method.

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Visual inspection 1/3

oTraditional Visual inspectionoVisual inspection by X-RAY based technology

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Visual inspection 2/3Traditional Visual inspection

• A typical suitable viewing apparatus may consist of a viewing station comprising:• — A matt black panel of appropriate size held in a vertical position,• — A non-glare white panel of appropriate size held in a vertical position next to the black panel,• — An adjustable lampholder fitted with a suitable, shaded, white-light source and with a suitable light

diffuser (e.g. a viewing illuminator containing two 13 Watt fluorescent tubes, each 525mm in length, is suitable). The intensity of illumination at the viewing point is maintained between 2000 lux and 3750 lux, although higher values are preferable for coloured glass and plastic containers.

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• Apparatus for visible particles.• Remove any adherent labels from the container and wash and dry the outside. Gently swirl or invert

the container, ensuring that air bubbles are not introduced, and observe for about 5 seconds in front of the white panel. Repeat the procedure in front of the black panel. Record the presence of any particles.

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Visual inspection 3/3Visual inspection by X-RAY based technology• Technological breakthroughs in the manufacturing of highly sensitive

large X-ray detector arrays has allowed WILCO scientists and engineers to design the latest visual inspection machines by coupling these arrays with customized X-ray tubes and sophisticated digital image processing.

• With this technology, one is able to detect defects such as:• • Cracks• • Foreign particles• • Functional defects

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Bubble tests 1/2

• The container (Ampoule,…) is submerged into a liquid.• A differential pressure is applied on the vessel.• Any leakage is evident after application of the vacuum by

foaming/bubbles.• Observation of bubbles can be optimized by using a surfactant

immersion fluid together with Dark background and hight intensity lighting

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Bubble tests 2/2

• In this test, the item under test is pressurized to about 3 psig and immersed in a bath containing water or water and surfactant (e.g., polysorbate 80).

• This test can detect leaks as small as 10-5 mbar-L/sec. Key test factors include differential pressure, test time, immersion fluid surface tension, visible inspection conditions (e.g., light intensity, magnification, and background), and visual inspector training and experience.

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Dye ingress test 1/4

• Historically, leak testing in the pharmaceutical industry has always involved some form of testing using the blue dye methodology.

This type of test has the relatively simple goal of determining whether a package/container leaks or not, by watching if the blue dye penetrates into the sealed container.

The inspection systems are studied in the minimum details and developed in order to meet any requirement of destructive testing of any kind of package, in particular such machinery are designed to test all the pharmaceutical containers such as vials, glass and plastic vials, ampoules, blister packs, BFS monodose, plastic strip, pouch containing IV solutions etc,

The technical features : Testing precision, speed, repeatability, silence, user friendliness, cleaning and maintenance simplicity, and low energy consumption.

• methylene blue dye solution. Both• positive and reduced pressure is applied to the chamber for• set periods. Samples are rinsed and visually examined for• the presence of blue dye.

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Dye ingress test 2/4

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Dye ingress test 3/4

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Dye ingress test 4/4

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Microbial ingress test Suitable for any container-closure system that can withstand immersion

and pressure changes (Mostly used for process validation). Microbial aerosols are also used for some packagings In the microbial immersion test, the test article is immersed in a broth

containing the test organism. This test may be static, in which no pressure or vacuum is applied, or

dynamic, in which pressure and vacuum are applied, typically to simulate air transport.

Key test factors include: bacterial size and motility, differential pressure, challenge media, exposure time, and viable count in the challenge media.

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Useful for testing leaks in preparations sealed under vacuum, such as lyophilized preparations

High voltage/high frequency field is applied to container to cause any possible residual glass to glow

Vacuum ionization test (Corona discharge test)

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Vacuum decay method (VDM) 1/2 Vacuum Decay Method (VDM): “Non-invasive, non-destructive physical method for inspecting Packages in a sealed Testing Chamber”

Principle of operation according to ASTM F2338

Useful for testing any nonporous package type (Vials, Pre-filled Syringes, BFS, FFS, etc) ASTM F2338-09

“Standard Test Method for Nondestructive Detection of Leaks in Packages by Vacuum Decay Method”

FDA (CDRH) Recognised Consensus Standard; >Recognition Number 14-282; Effective date 2006 March 31st

Vacuum is established within a sealed Test Chamber, with Package inside; Vacuum is disconnected and Test Chamber is allowed to stabilize; Leaks are identified by measuring the Vacuum level change.

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Vacuum decay method (VDM) 2/2

[*] Decision making: 

o Δ ≤ THR à GOODx Δ > THR à REJECT  (Small Leak)x 1st < Min Level à REJECT (Large Leak) 

Bonfiglioli Engineering and Continuous Improvement Manager at Novartis Vaccines, authored an article on presenting an unprecedented case study conducted on Pre-filled Syringes, published on the 2015 January/February issue of PDA Journal of Pharmaceutical Science and Technology. Vacuum Decay, Pharmacopoeial Dye Ingress Test, Novartis Specific Dye Ingress Test and High Voltage Leak Detection were, in succession, the methods involved in the comparative studies. Results showed that Vacuum Decay method had the highest performance in terms of detection sensitivity and also ensured the best reliability and repeatability of measurements.

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Pressure decay method (PDM)100% In-Line and Off-line CCIT: Pressure Decay Method: “Non-invasive, non-destructive physical method for

inspecting Packages in a sealed Testing Chamber” PDM is long since one of the most widely used method of leak testing Useful for testing any nonporous package type PDM is preferred to VDM when dealing with of oil-based product

(high viscosity / density)

Principle:Pressure is established within a sealed Test Chamber, with Package inside.Pressure is disconnected and Test Chamber is allowed to stabilize.Leaks are identified by measuring the Pressure level change

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Force sensor technology, FS for flexible bags• For flexible packages like IV bags a a non-

destructive system is developed using precise and highly sensitive force sensors. This technology is applied combining mechanical forces, squeezing, or vacuum forces, generated with a vacuum pump.

Short cycle times of less than 10 secondsEasy handling with high process securityFully validatable systemEasy calibrationFor IV Bags applications, single station as well as high

capacities machines Achieving leak sensitivities above 150 microns.

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Mass spectrometry, MSLeak detection in ppm or ppb levels using customized mass

spectrometry arrangementsFor leak detection cases where a specific gas type or very small gas

flow-rate needs to be detected, combine leak detection technology and engineering to provide customized mass spectrometry solutions for clients.

The system’s sensitivity varies between parts per million (ppm) and parts per billion (ppb) for the detection of gases escaping containers such as oxygen, carbon dioxide and alcohol vapor.

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Liquid filled container, LFC WILCO method Measuring the loss of vacuum inside a test chamber as a result of gas leakage or liquid

vaporization from a leak. The LFC testing method is a powerful leak detection technology, which measures the loss of

vacuum inside a test chamber as a result of gas leakage or liquid vaporization from a leak. Since the vaporization of even a very small amount of liquid causes a large increase in

pressure in the small test chamber, the sensitivity of this method is significantly greater than for a standard vacuum decay method.

The application of a testing pressure below the equilibrium vapor pressure of water (at 20°C, 23.3 mbar) is under WILCO patent.

For any liquid filled container either glass or plastic, this technology provides accurate results at high test capacities for the following containers:

Pre-filled syringes Single or Dual Chamber cartridges Liquid filled vials BFS ampoules

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High Voltage Leak Detection(HVLD); High Voltage Spark test 1/4

High Voltage Leak Detection System (HVLD) is the most reliable, repeatable and productive inspection method having the following advantages:

Detectability of 1 micro meter or smallerNon-destructive Inspection MethodNo secondary contamination to the product100 percent inspection at higher production speeds with increased reliability

Principle of Inspection: High voltage is applied to a hermetically sealed container made of non-conductive material. If pinhole or crack is present on the ampoule, the discharge current fl ows into the ampoule

through the pinhole or crack. The defective ampoule is detected by the differential of the current fl ow as measured in the

intact ampoule.

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High Voltage Leak Detection (HVLD); High Voltage Spark test 2/4

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High Voltage Leak Detection (HVLD); High Voltage Spark test 3/4

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High Voltage Leak Detection (HVLD); High Voltage Spark test 4/4

Crystallization of product within a micro crack, at normal atmospheric pressure, detected 100% by HVLD

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10 Criteria for choosing the suitable leak test 1/10

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10 Criteria for choosing the suitable leak test 2/10

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10 Criteria for choosing the suitable leak test 3/10

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10 Criteria for choosing the suitable leak test 4/10

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10 Criteria for choosing the suitable leak test 5/10

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10 Criteria for choosing the suitable leak test 6/10

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10 Criteria for choosing the suitable leak test 7/10

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10 Criteria for choosing the suitable leak test 8/10

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10 Criteria for choosing the suitable leak test 9/10

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10 Criteria for choosing the suitable leak test 10/10

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Calibration-Validations of the method/machinery-Trainings 1/2

All test methods need to be validated or consistently verified for accuracy. This is typically done by introducing a number of defects of known size or leak rate as controls to establish the linear range and repeatability of the leak test.

Calibrated leaks can be established by using laser-drilled holes, calibrated Orifices, or through introducing wires of a know size between the closure and the sealing surface (3). The detection limit of the leak test can be determined per ICH Q2 (R1).

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Calibration-Validations of the method/machineryTrainings 2/2

TEST KIT FOR SYSTEM VERIFICATION Test kit set is to be made according to the

product shape and weight to simulate good and bad signals at each inspection zone. It is used for daily validation of the machine to test the inspection performance of each inspection electrode as well as the general functionality of the system.

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Regulatory requirements for CCIT and Particulate matter 1/13

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Regulatory requirements for CCIT and Particulate matter 2/13

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Regulatory requirements for CCIT and Particulate matter 3/13

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Regulatory requirements for CCIT and Particulate matter 4/13

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Regulatory requirements for CCIT and Particulate matter 5/13

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Regulatory requirements for CCIT and Particulate matter 6/13; Revisions to USP<1207> underway

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Regulatory requirements for CCIT and Particulate matter 7/13; Revisions to USP<1207> underway

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Regulatory requirements for CCIT and Particulate matter 8/13

• 100% inspection of injectable products including: cracks, visible particles and other significant defects.

• Verify the firm has written procedures that define the defects to be removed from the lot and actions to take if the number of critical defects exceeds a pre-determined level.

• Significant defect categories should be identified. Results of inspection of each batch should be compared to established action levels.

• Evaluate the appropriateness of and the rationale or justification for pre-determined action levels. • Evaluate the firm’s investigation into the cause of rejects, including units rejected for cracks and

visible particulates (e.g., foreign matter). Observe the inspection process.

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Regulatory requirements for CCIT and Particulate matter 9/13

Packaging defect classification per FDA:• Class I Defects: Defined as Critical Defects. Class I defects are gross

defects that may be a channel leaker, a cut, fracture, non-bonding seal, notch leaker, puncture.

• Class II Defects: Defined at Major. These defects show no sign of visible leakage, but these defects have compromised the sterility of the product. Abrasions, blisters, delamination, micro crack, pinhole, seal variation, seal misalignment.

• Class III Defects: Defined as a defect that has no adverse effect on the hermetically sealed container. These defects may be cosmetic.

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Regulatory requirements for CCIT and Particulate matter 10/13• Challenge visual/manual inspection rates through observation. • Evaluate the adequacy of written procedures for visual inspection. • Evaluate personnel qualification and requalification and equipment qualifications according to

established procedures. Evaluate personnel qualification including the use of reference samples for qualification.

• If a manual system is used, determine if employees are trained and qualified to verify they can recognize and remove defects under actual or simulated production conditions.

• If an automated or semi-automated system is used, determine the equipment is qualified and the software program or equipment settings have been validated for all types of products being inspected (e.g., clear vials, amber vials, colored solution, suspensions).

• If the equipment is an automatically controlled computer based system, an assessment of the system and validation is warranted.

• Evaluate the firm’s program for sampling and examination of inspected vials and evaluate the effectiveness of inspection and action taken if the reject level is reached.

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Regulatory requirements for CCIT and Particulate matter 11/13• Evaluate the firm’s assessment of units rejected during filling operations (any

separate inspection prior to the 100% inspection stage), established alert/action limits, and investigations where appropriate.

• Container-closure integrity testing should be a component of stability testing for new and existing products.

• The FDA Guidance on Container-Closure Integrity Testing in Lieu of Sterility Testing encourages companies to use container-closure integrity testing to replace sterility testing in stability protocols

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Regulatory requirements for CCIT and Particulate matter 12/13• Evaluate the firm’s assessment of units rejected during filling operations

(any separate inspection prior to the 100% inspection stage), established alert/action limits, and investigations where appropriate.

• Container-closure integrity testing should be a component of stability testing for new and existing products.

• The FDA Guidance on Container-Closure Integrity Testing in Lieu of Sterility Testing encourages companies to use container-closure integrity testing to replace sterility testing in stability protocols.

• A non-destructive test is especially useful for stability testing, as it allows the same container to be tested multiple times over the stability period.

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Regulatory requirements for CCIT and Particulate matter 13/13• This reduces the number of stability samples and allows more

meaningful profiles of container-closure integrity.

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References 1/2• USP38<1207> Container Closure Integrity Test• http://atcinc.net/usp-updates-leak-testing-recommendations-for-pharmaceutical-companies• http://www.pharmaceuticalonline.com/doc/usp-general-chapter-revisions-industry-experts-offer-

best-practices-to-avoid-destructive-unreliable-integrity-testing-0001• Sterile Product Package Integrity Testing Current Practice, Common Mistakes, New Developments;

Dana Morton Guazzo, PhD; PDA Metro Chapter; May 17, 2010• Proposed revisions to USP <1207> STERILE PRODUCT - PACKAGE INTEGRITY EVALUATION; PDA

Europe Parenteral Packaging Conference; Brussels, Belgium 11 Mar2014; Dana M. Guazzo Ph.D.; USP Packaging Storage and Distribution Expert Committee

• https://nikkadensokusa.files.wordpress.com/2015/04/sterile-product-packaging-by-pda.pdf• www.nikkadensok.com• www.wilco.com• www.bonfiglioliengineering.com• www.pharmtech.com/evaluating-package-integrity

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References 2/2

• www.pharmtech.com/evaluating-package-integrity• https://nikkadensokusa.files.wordpress.com/2015/04/sterile-product-packaging-by-pda.pdf• http://

www.pda.org/docs/default-source/website-document-library/chapters/presentations/new-england/pda-technical-report-43-(revised).pdf?sfvrsn=6

• https://www.aluglas.com/en/knowledge-glass-lexicon-moulded-glass-bottle-lexicon-image?serverid=aluen

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Inspector Jacques Clouseau looking for leaks!Any questions?