Container Closure Integrity Testing
Container Closure Integrity Testing (CCIT)
Container Closure Integrity Testing (CCIT) is an assay that evaluates the adequacy of container closure systems to maintain a sterile barrier against potential contaminants. Contaminants that could potentially cross a container closure barrier include microorganisms, reactive gases, and other substances. Container closure systems should maintain the sterility and product quality of sterile final pharmaceutical, biological, and vaccine products throughout their shelf life.
This CCIT can be divided into two major categories,
1) Deterministic
2) Probabilistic
Deterministic methods are less subject to error and provide quantitative results. Probabilistic methods are more uncertainty in the assay results and include the more traditional methods of testing
The deterministic methods include the following:
- Electrical Conductivity and Capacitance Test (HVLD)
- Laser-based Gas Headspace Analysis
- Mass Extraction
- Pressure Decay
- Tracer Gas (vacuum mode)
- Vacuum Decay
The Electrical Conductivity and Capacitance Test
The Electrical Conductivity and Capacitance Test- is also known as High Voltage Leak Detection (HVLD).
This assay looks for leaks in walls of nonporous, rigid or flexible packaging containing liquid or semi-liquid product (e.g. ampoules).
During the assay, a high voltage and high frequency charge is applied across the container closure system.
A detected leak will cause an increase in current across the high voltage electrodes, triggering the reject mechanism for the leak detector.
Key factors for the assay include the voltage level, probe positioning, the container-closure system geometry, the wall thickness, and the product formulation
LASER BASED GAS HEADSPACE ANALYSIS
LASER BASED GAS HEADSPACE ANALYSIS is typically performed using non-contact methods, such as frequency modulation spectroscopy.
During the assay, a near infrared diode laser light passes through the gas headspace region.
The light is absorbed as a function of gas concentration and pressure.
This absorption information is processed using phase-sensitive detection techniques.
A microprocessor analyzes the data and yields the test results.
The Laser-based Gas Headspace Analysis can be used for lyophilized products or oxygen-sensitive liquid products.
The gas analysis of the headspace is rapid, on the order of seconds.
This method allows for 100% inspection of oxygen sensitive products or products packaged under vacuum.
The test is nondestructive and provides quantitative results.
Key parameters for the assay include the headspace volume, the package temperature, the headspace pressure, vacuum, and the sensitivity of the headspace analysis instrumentation.
MASS EXTRACTION ASSAY
The Mass Extraction assay is nondestructive and quantitative.
It can be used for detecting leaks in nonporous, rigid or flexible packages.
Packages with a porous component can be tested with the mass extraction assay by masking the porous package component.
The assay is performed by placing the test sample inside a test chamber that is pneumatically connected to a mass extraction leak test system equipped with a vacuum generator package.
The chamber is quickly evacuated for a predetermined time to reach a predetermined vacuum level.
A series of evacuation cycles are performed, each intended to identify smaller leakage rates.
After each cycle, the test system is isolated from the vacuum source and measurements of absolute pressure, pressure decay rate, and/or gas mass flow rate are captured.
Readings that are greater than the predetermined limits that were established using negative controls are indicative of container leakage.
These readings will trigger the test cycle abort.
For those test samples passing all previous larger leak vacuum cycles, a final vacuum is drawn.
The mass flow rate is measured with all of the flow from the test chamber directed through the mass flow sensor.
Mass flow that is above a predetermined limit established using negative controls is indicative of container leakage.
The PRESSURE DECAY TEST is intended for integrity testing of the gas headspace region of the test sample (nonporous, rigid, or flexible packages).
For this test, the container-closure system is placed in a test fixture that is either pressurized or evacuated.
The test chamber is allowed to stabilize, and then the change in pressure or vacuum is measured over time.
Pressure or vacuum can be measured directly or by the differential pressure between the test chamber and a reference chamber.
The key test parameters include the temperature, the package geometry, the test fixture geometry, the volume of package headspace, the water vapor pressure inside the package, the stabilization time, and the test time.
The TRACER GAS TEST (Vacuum Mode) – detects leakage from nonporous, rigid or flexible packages.
The test requires the presence of a tracer gas inside the test sample package.
Helium is the most commonly used tracer gas but, hydrogen can also be used.
The leakage rate of the tracer gas is quantitatively measured using a spectrometric analytical instrument specific for the tracer gas.
VACCUM DECAY
VACCUM DECAY- to perform the vacuum-mode test, the test samples that have been fully or partially flooded with tracer gas are placed inside an evacuation chamber.
The instrument’s vacuum pump evacuates the test chamber or fixture, drawing any leaking tracer gas through the analyzer.
The absolute leak rate of the test sample may be calculated by normalizing the test results by the partial pressure of the tracer gas within the test sample at the time of test.
The test sample leakage is judged acceptable if the absolute leak rate is below that which has been reported to put the product quality at risk.
The Vacuum Decay method is a nondestructive and quantitative assay.
It detects leaks in nonporous, rigid or flexible packages. Packages with a porous component can be tested by masking the porous package component.
The test sample is placed in a closely fitting evacuation test chamber, which is equipped with an external vacuum source.
The test chamber plus test system dead space are evacuated for a predetermined period of time.
The targeted vacuum level chosen for the test is predetermined on the basis of the test sample type under evaluation.
The rise in dead space pressure (i.e., vacuum decay) is monitored for a predetermined length of time using absolute and/or differential pressure transducers ‘A pressure increase that exceeds a predetermined pass/fail limit established using negative controls indicates container leakage.
The probabilistic methods include following:
- Microbial Challenge by Immersion
- Tracer Liquid Tests (e.g. Dye Ingress)
- Bubble Tests
- Tracer Gas (Sniffer Mode)
The microbial challenge by immersion and the dye ingress test are the most recognized leak test methods.
The update series is encouraging a move toward the deterministic methods.
MICROBIAL CHALLENGE BY IMMERSION TEST
The microbial challenge by immersion test is suitable for any container closure system that can withstand immersion and pressure changes.
The test article is immersed in a broth containing the test organism.
Brevundimonas diminuta, Escherichia coli and other organisms have been used for this test.
The test performed in a static mode, where no pressure or vacuum are applied, or in a dynamic, where pressure and vacuum be are applied.
The purpose of the dynamic mode is typically to simulate air transportation of the product.
Key test factors for the assay include the bacterial size and motility, the differential pressure, the challenge media, the exposure time, and the viable count of the microorganism in the challenge media.
DYE LEAK TEST
The dye leak test is the most common liquid tracer assay.
The container is immersed in a methylene blue solution and pressure and vacuum are applied to the container.
The containers are inspected visually or via spectrophotometry (preferred method) to observe for traces of blue dye in the container.
The key factors for this test include the differential pressure, the compatibility of the dye with the product, the liquid viscosity and surface tension, the training and experience of the inspector (for visual inspection), and the assay sensitivity( for spectrophotometry)
Ø Any leak test requires optimization for each product-package application. All methods have limitations, but the following aspects should be considered when choosing a suitable method:
- Methods must be suitable for its intended use
- Methods must be applicable to the specific drug product package (e.g. drug products can interact with CCI defects)
- Methods must detect leaks effectively
- Non-destructive CCI testing
Test method selection, development and validation
Why is CCIT method development and validation critical? no one CCIT method is applicable to or compatible with all product package configuarations.
Controls, masters and blanks
Negative controls
Product filled packages with no known leak (min of 30)
Used to demonstrate method performance and or baseline signal
Positive controls
Product filled packages with a simulated leak
Used as system suitability checks for some methods
Masters
No leak container closure model used as a system performance check
Blanks
Used to establish a methods basline performance
Not negative controls
SOME OF THE OPTIONS TO GENERATE SOME POSITIVE CONTROLS ARE
GENERAL METHOD DEVELOPMENT APPROACH
q OPTIMIZING STARTING PARAMETERS
Use positive and negative controls to establish test parameters
q FEASIBILITY AND ROBUSTNESS
- Perform a minimum of three different analytical runs
- Calculate mean, max, and standard deviation for negative and positive control results
- Set estimated rejection limit based upon 6sigma and 8sigma of the negative controls
- Apply slight variations in critical parameters to evaluate robustness
GENERAL METHOD VALIDATION APPROACH
Accuracy
Accuracy of this method is shown by demonstrating the ability to Differenciate samples with defects greater than the established detection limit from samples with defects less than the established detection limit
Range
The interval between the smallest and largest leak size or rate can be detected by the method with a suitable level of accuracy and precision
Specificity
The ability of the method to differentiate between leaking and non-leaking packages, despite entering factors that may cause false detection
Detection limit
The smallest leak size or defect size that the method can reliably detect.
Precision
The methods ability to produce reliable repeatable data
- Within same laboratory with multiple analyst over multiple days
- Test among multiple laboratories
Quantitation limit
The lowest leakage rate that can be differentiated with accuracy and precision under the stated experimented conditions
Linearity
The ability of the method to generate test results that are mathematically proportional to leakage rate
Stability Testing
- The routine testing SOP should be utilized when performing CCIT for stability testing.
- Container-closure integrity should be demonstrated as part of the stability program over the shelf life of the product for new and existing product
- Container closure integrity testing may not replace the sterility test for release testing.
- However, container-closure integrity testing can be used to replace sterility testing in stability protocols.
- The sterility testing or alternatives (e.g. container/closure integrity testing) should be performed minimally at the initial time point and at the end of the proposed shelf-life.
- It is highly recommended to do interim time points in case a time point does not pass specifications.
- Some companies perform stability testing on a yearly basis until the end of the stability study.
- If a non-destructive test has been validated for the specific containerclosure system, it is useful during stability studies.
- The same container can be used throughout the stability period.
- This saves money and allows for more meaningful profiles of container-closure integrity
- Bracketing is also a useful strategy in stability studies, when the same strength and exact container/closure system is used for 3 or more fill contents, the manufacturer may elect to place only the smallest and largest container size into the stability program.
- This strategy will save time, money, product, and room in the stability chambers.
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