Container Closure Integrity Testing (CCIT) (2023)

Container Closure Integrity Testing (CCIT) (1)

The integrity of container and closure systems is crucial to product and patient safety. The container must be able to prevent product loss and ensure product sterility.

The revision of General Chapter 1207 of the United States Pharmacopoeia has set the first standards for non-destructive technologies.
The integrity of container and closure systems is crucial to product and patient safety. The containermust be able to prevent product loss, ensure product sterility and, if necessary, prevent the ingress of oxygen or maintain negative pressure in the headspace. If leaks are not detected before the medication is administered, they can pose a serious risk to patients. In fact, they pose an even greater risk than particles in pharmaceutical liquids: they can alter the active pharmaceutical ingredient. Possible consequences are ineffective drugs or unwanted side effects.

Sterility violations can be identified using suitable test methods before product contamination occurs – which significantly improves patient safety. Container Closure Integrity Testing (CCIT) not only reduces the risk of product recalls. It also proves to be more time-saving and less expensive than most sterility testing methods.

(Video) Container Closure Integrity Testing | CCIT

Probabilistic or deterministic?

The revision of General Chapter 1207 of the United States Pharmacopoeia (USP) aims to provide an overview of the common CCI test methods and to identify those that contribute most to product and patient safety. CCI test methods are divided into probabilistic or deterministic methods. Probabilistic methods rely on qualitative information including human judgment. Deterministic methods, on the other hand, are quantitative and therefore less error-prone. Furthermore, Chapter 1207 distinguishes between destructive and non-destructive methods. The methylene blue test, for example, is a classic probabilistic, destructive procedure in which the packaging is immersed in blue-colored water. The method not only renders the product unusable, but also proves prone to human error.

Preferred deterministic methods include non-destructive technologies that protect the often expensive product within the container. Nevertheless, the various authorities are unlikely to issue a recommendation for a single technology. Each product and each manufacturing process requires a careful selection of the existing methods and can consist of more than one technology for the respective process steps. In addition, with new packaging formats and pharmaceutical formulations, regulations need to be expanded beyond their current scope. According to Appendix 1 of the European GMP, sealed containers, such as glass or plastic ampoules, should be subjected to a 100% integrity check.

(Video) Container Closure Integrity Testing | CCIT Parenterals | Vacuum & Pressure Decay | Sepha Multi-Q

The actual process of filling vials is already proving to be particularly demanding in terms of product sterility and packaging integrity. The stopper is placed on the vial but not immediately sealed. This exposes the contents to potential contamination.

Focus on packaging and lyophilization

But not only ampoules are prone to leaks or breaches of sterility. Vials, syringes and cartridges make even greater demands on the integrity of containers and closures because they are made up of different components. This also increases the risk. For example, a vial consists of a glass container, a stopper and a closure. Here, all parts of the container and closure system must be thoroughly inspected at all levels.

With regard to drug development and test requirements, freeze-dried products play a central role in drug manufacture. Numerous new parenteral products, including anti-infectives, biotechnological products and in vitro diagnostics are freeze-dried. During lyophilization, the product is frozen and placed under vacuum before being subsequently dehydrated. In this way, the ice changes directly from the solid to the gaseous state without liquefying. The process consists of three different steps: deep freezing, followed by primary and secondary drying. Each process step has its own risks and requires very precise control of both the product and the container and closure system.

In the KLD inspection machine, cracks in the container are identified using a high-voltage test.


100% control so far for ampoules - changes expected

The actual process of filling vials is already proving to be particularly demanding in terms of product sterility and packaging integrity. The stopper is placed on the vial but not immediately sealed. This exposes the contents to potential contamination. In addition, imprecisely placed stoppers or closures, fibers on the rim of the vial, or stoppers and vials that do not perfectly match can lead to further defects. Cracks in the container glass, improper handling or incorrectly adjusted machines can also cause leaks. In fact, the reject rates for freeze-dried vials can be identical to those for ampoules. The main difference is that a 100% CCI inspection is only required for ampoules, but not for other types of containers. However, numerous experts expect that the guidelines will soon be adjusted accordingly.

Numerous deterministic, non-destructive methods are already available on the market today. Accordingly, there is no need to develop completely new technologies. Instead, the way in which the industry evaluates and applies these methods is changing. Drug manufacturers are encouraged to use technologies that significantly increase quality assurance and testing rates. The technology used for leak testing depends on the specific product and container properties, such as conductivity, headspace parameters, alcohol content and active pharmaceutical ingredients.

The AIM 3 inspection machine presented in 2015 combines the visual inspection of the AIM series and the high-voltage leak test of the KLD series. The AIM 3 inspects ampoules and vials filled with solutions and suspensions at an output of up to 400 containers per minute.

Wide range of CCI technologies

The leak test, which is carried out using high voltage, detects leaks in the container wall, for example in parenteral vials, prefilled syringes and cartridges. The test method is based on the quantitative measurement of the electricalConductivity. Using conductive solutions, the electrical resistance of containers is measured at currents of up to 25 kilovolts, which decreases sharply when there are leaks. Another non-destructive method is the measurement of vacuum or pressure drop. This is suitable for identifying leaks in packaging, such as liquid dosage forms, freeze-dried products and dry powders. For this purpose, a quantitative measurement of the pressure increase or decrease that occurs in the event of headspace leaks or evaporation of liquid products is carried out.

(Video) Laser based Headspace Analysis as a Container Closure Integrity Testing Tool

Headspace analysis is useful for freeze-dried products and pharmaceuticals that have been vacuum-filled or gas-cleaned. Using laser spectroscopy, she measures the amount of light that flows through the headspace and checks changes in the gas composition in the headspace or its total pressure. Leaks allow gas from outside the canister to enter the headspace. If a container is originally processed with a changed atmosphere in the headspace, a correlation can be established between an overall increase in pressure or a partial increase in oxygen pressure and a leakage rate.

With the KLV 1360, Bosch is presenting a new development for vacuum testing stable containers at the Interpack. This is characterized above all by the combination of very high inspection accuracy with maximum output. (Pictures: Bosch)

Selection of the appropriate test method depends on the product and the packaging

In order to determine the appropriate test method for each product and container, comprehensive product knowledge is essential: Is the product sensitive to oxygen or moisture? Does it require a specific vacuum value? How is the molecule structured? What critical defect size must be identified to ensure sterility and integrity of a product throughout its shelf life? Thanks to the careful selection of appropriate technologies, drug and system manufacturers can work together to find suitable solutions that also meet the latest regulatory requirements. Experienced machine manufacturers such as Bosch Packaging Technology can provide valuable support and assume the role of provider, consultant and partner in one person.

Bosch already has a comprehensive range of methods for visual inspection and CCI control. The KLV 1360, presented for the first time at the Interpack, completes this portfolio. The new development is for the vacuum test of stable containersdesigned and is characterized above all by the combination of a very high inspection accuracy with maximum output. In addition to fully automatic solutions for leak testing using high voltage and laser-based headspace analysis, all CCI technologies can be offered through the portfolio expansion.

(Video) CDV Pharma 💊 Blister Blue Dye Leak Testing - Container Closure Integrity Testing CCIT

Interpack: Halle 6, Stand A30-C58


Container Closure Integrity Testing (CCIT)? ›

Container Closure Integrity Testing (CCIT) is an assay that evaluates the container closure and its ability of maintaining a seal to keep potential contaminants out. Potential contaminants include microorganisms, reactive gases, and other substances.

What is the Ccit test method? ›

Container Closure Integrity Testing Method requires the creation of positive and negative controls, taking into consideration the design, material, expected package leak features and content. This is done to mimic defects and is inspected together with the intact samples.

What are the acceptance criteria for container closure integrity test? ›

Acceptance criteria for leak test method validation should include the following: All negative controls pass (no leaks are identified) (USP <1207.1>). All positive controls with leaks at or above the designated limit of detection fail (leaks are detected) (USP <1207.1>).

What is the USP 1207 test method? ›

USP Chapter 1207 provides an overview of common CCIT tests and categorises them as being deterministic or probabilistic. The chapter states a preference for deterministic tests on the basis that they are non-invasive, produce repeatable and predictable results and are suited to 100% testing.

What is the difference between deterministic and probabilistic Ccit? ›

Unlike deterministic test methods which are based on measurable physicochemical technologies, a probabilistic test method only gives subjective and qualitative outcomes. Also, most probabilistic test results are visually assessed, hence subject to bias due to variation in a technician's experience and skills.

What is the sample size for Ccit? ›

Typically, a zero-acceptance sampling plan may be used, where a total of 20 finished product samples are considered as a minimum sample size also for routine testing of CCIT.

What is vacuum decay method for CCIT? ›

Vacuum Decay is a non-destructive CCI testing method that focuses on package integrity and leak path detection. Unlike manual inspection and other non-deterministic testing techniques, Vacuum Decay provides quantitative, deterministic, and accurate test results to assure package integrity.

How do you test seal integrity? ›

For the positive pressure method of this test, an operator injects helium into a sealed package or adds helium to the package headspace upon sealing. After this, a mass spectrophotometer is used to identify and quantify the presence of helium in the surrounding enclosed space.

What are the requirements of good container and closure? ›

The ideal container-closure will have low permeability to air and moisture and a high resistance to aging (2).

What is acceptance criteria checklist? ›

What are the Acceptance Criteria? In short, acceptance criteria are the conditions that a specific user story must satisfy to be considered as completed, you may think of them as a checklist that helps verify if a coding team built the right feature and whether it is completed correctly.

What is USP 671 method 5? ›

Method 5 is a required classification test for multiple unit solid oral dosage form (SODF) plastic packages; either those without an impervious (induction) seal, or those that will have an end-use and storage period with an open (broached) induction seal.

What are the test methods that is found in the USP? ›

USP testing specifications include checking for sterility, bioburden, and endotoxin. These predetermined processes are used by a collection of industries in the country. Some USP testing methods consist of standards that make it universally beneficial to develop safe products.

What is the USP limit test? ›

USP <61> is often called a "Bioburden" or "Microbial Limits" test. This test determines how many microorganisms are present in non-sterile drug products. During a USP <61> test, a sample is prepared and plated on two types of growth media (Soybean-Casein Digest Agar and Sabouraud Dextrose Agar).

What is deterministic vs probabilistic vs stochastic? ›

In deterministic models, the output of the model is fully determined by the parameter values and the initial values, whereas probabilistic (or stochastic) models incorporate randomness in their approach. Consequently, the same set of parameter values and initial conditions will lead to a group of different outputs.

Which is better deterministic or probabilistic? ›

While deterministic data is consistent, more accurate and always true, it can be hard to scale. Probabilistic data can solve the issue of scalability, but can be less precise. Therefore, most data management and marketing professionals combine both types of data to get the most valuable insights.

What is an example of deterministic vs probabilistic? ›

Deterministic: All individuals with Smoking = 1 have Cancer = 1. Probabilistic: Individuals with Smoking = 1 have higher likelihood of having Cancer = 1.

What does C 0 mean in AQL? ›

Acceptance sampling is used to assess the quality based on sample size, acceptance number, and desired quality level. C=0 sampling plans are based on the premise of accepting the lot if zero defects are found during the inspection, and rejecting the lot if one or more defects are found during the inspection.

What is the difference between AQL and C 0? ›

These plans are designed to give (roughly) a 95-percent chance of acceptance at the acceptable quality level (AQL), which is one of the parameters for the plan's selection. The c = 0 plan, on the other hand, rejects the lot if any defects or nonconformances are found, but it requires a considerably smaller sample size.

What is acceptable sample size? ›

A good maximum sample size is usually around 10% of the population, as long as this does not exceed 1000. For example, in a population of 5000, 10% would be 500. In a population of 200,000, 10% would be 20,000. This exceeds 1000, so in this case the maximum would be 1000.

What can trigger vacuum decay? ›

For the vacuum to decay, it must be possible to build a bubble of total energy zero. In the absence of gravitation, this is no problem, no matter how small the energy-density difference; all one has to do is make the bubble big enough, and the volume/surface ratio will do the job.

Is vacuum decay inevitable? ›

As long as decay is possible, it's inevitable. At any instant in time there's a tiny but real probability that a patch of space will tunnel between the false and true vacuums. Wait long enough and it WILL happen.

How do you do a vacuum decay test? ›

To conduct a vacuum decay test, a container is placed in a tightly fitted chamber which is evacuated to a predetermined level of vacuum. After reaching the pre-set vacuum, a sensor measures the vacuum level over a predetermined time.

What is an integrity test example? ›

Typical covert integrity questions include: True or False: I don't like people telling me what to do. True or False: I consider myself a risk-taker. True or False: I find it hard to make connections with the people around me.

What is required for seal integrity? ›

Seal Integrity . A continuous seal with no bubbles, blisters or other inconsistencies as per WB-10-02-06 and WB-10-02-02. If channels are observed during the dye penetration test, a minimum seal width of 7 mm must be maintained to accept the results.

What is the ASTM method for package integrity? ›

ASTM F1886 is the standard test method for determining the integrity of seals for flexible packaging by visual inspection. Specifically, this ASTM package validation standard covers the determination of channels in the package seal down to a width of 0.003 inches.

What is the IICL standard for containers? ›

IICL stands for "International Institute of Container Lessors". Essentially, the IICL has created a standard of inspection that insures that an ISO Storage Container is in adequate condition to be long-term leased for cargo transportation.

What are the four attributes of a container closure system that may need to be evaluated? ›

FDA�s guidance document requires the evaluation of four attributes to establish suitability: protection, compatibility, safety, and performance/ drug delivery2.

What are the three types of seals or closures of glass containers? ›

An o-ring or a closure liner is often used to maintain a seal. Linerless closures typically use a deformable plastic rim or structure. Secondary seals are commonly used with sensitive products that may deteriorate or where extra security is needed. Foil or plastic inner seals are used on some bottles.

Which are the basic two types of acceptance criteria? ›

There are two distinctive approaches to writing acceptance criteria: scenario-based and rule-based. Each one takes a slightly different focus and has its own set of appropriate use cases. However, both can play a key role in defining user requirements and design goals.

What is the difference between DoD and acceptance criteria? ›

Definition of Done (DoD) is a list of requirements that a user story must adhere to for the team to call it complete. While the Acceptance Criteria of a User Story consist of set of Test Scenarios that are to be met to confirm that the software is working as expected.

Who should perform UAT testing? ›

Who performs UAT? End users normally perform user acceptance testing. They are the most effective group to test software in this form because they know exactly how the software will be used on a daily basis and what changes need to be made to be suitable for this day-to-day use.

What is USP 661? ›

USP 〈661.1〉 “Plastic Materials of Construction” introduces more rigorous standards and testing to demonstrate that polymer raw material is well-characterized and suitable for its intended use.

What is USP NF standard? ›

The United States Pharmacopeia – National Formulary (USP-NF) includes over 5000 quality standards for medicines, both chemical and biologic; active pharmaceutical ingredients (APIs); and excipients (inactive ingredients). It is the most comprehensive source for medicine quality standards in the world.

What is USP guidelines? ›

USP Official Reference Standards

USP offers over 7,000 USP Reference Standards, highly characterized physical specimens of drug substances, excipients, food ingredients, impurities, degradation products, dietary supplements, compendial reagents, and performance calibrators.

What are the three types of known test techniques? ›

There are three different testing techniques available. They include white-box testing, black-box testing, and grey-box testing. Let's discuss each of these techniques.

What are the four basic methods of product testing? ›

The four fundamental methods of verification are Inspection, Demonstration, Test, and Analysis. The four methods are somewhat hierarchical in nature, as each verifies requirements of a product or system with increasing rigor.

What is USP apparatus 4 method? ›

Flow-Through Cell Dissolution Tester (USP Apparatus 4)

The USP apparatus 4 comprises of a media reservoir to hold the dissolution media, a pump that forces the media upwards through a vertically positioned flow-through cell that holds the dosage form and a water bath to maintain the cell temperature.

What is the difference between USP 51 and 61? ›

For instance, USP <51> is chapter 51, which covers preservative effectiveness testing. USP <61> is the chapter that describes microbial examination of nonsterile products. The method can be used to assess the microbiological quality of everything from face lotion to a diagnostic reagent.

What is the difference between USP 61 and 62? ›

USP <61> testing includes an enumeration plate count and suitability testing, which validates the plate count. USP 62 testing evaluates the presence or absence of specific organisms.

What is the USP method validation 1226? ›

USP <1226>

The verification process for compendial test procedures is the assessment of whether the procedure can be used for its intended purpose, under the actual conditions of use for a specified drug substance and/or drug product matrix.

Why is stochastic better than deterministic? ›

While both techniques allow a plan sponsor to get a sense of the risk—that is, the volatility of outputs—that is otherwise opaque in the traditional single deterministic model, stochastic modeling provides some advantage in that the individual economic scenarios are not manually selected.

Is Monte Carlo simulation a stochastic process? ›

The Monte Carlo simulation is one example of a stochastic model; it can simulate how a portfolio may perform based on the probability distributions of individual stock returns.

What are the disadvantages of stochastic models? ›

The primary disadvantage of stochastic methods is that their accuracy is not very good, though it's usually close enough. For this reason they are typically not used when another method is feasible. The other disadvantage of stochastic methods is without computer assistance, they are slow.

Is AI A probabilistic or deterministic? ›

Conversational AI, on the other hand, is probabilistic. It relies on machine learning, natural language processing, deep learning, predictive analytics, and other language models to produce dynamic responses.

Is pert probabilistic or a deterministic? ›

PERT is a probabilistic model i.e. It takes into account uncertainties involved in the estimation of time of a job or an activity.

Is stochastic the same as probabilistic? ›

In general, stochastic is a synonym for probabilistic. For example, a stochastic variable or process is probabilistic. It can be summarized and analyzed using the tools of probability. Most notably, the distribution of events or the next event in a sequence can be described in terms of a probability distribution.

What is an example of stochastic vs deterministic? ›

For example, probabilities for stochastic models are largely subjective. One person might assign the odds of flipping a coin as a deterministic 50/50 chance of getting heads. Another person might say that that would happen only when the coin is perfectly balanced and fair, so a stochastic model might be appropriate.

What is a simple example of deterministic model? ›

Deterministic models assume that known average rates with no random deviations are applied to large populations. For example if 10,000 individuals each have a 95% chance of surviving 1 year, then we can be reasonably certain that 9500 of them will indeed survive.

What is a probabilistic model simple example? ›

For example, if you live in a cold climate you know that traffic tends to be more difficult when snow falls and covers the roads. We could go a step further and hypothesize that there will be a strong correlation between snowy weather and increased traffic incidents.

How do you conduct a structural integrity test? ›

How to Calculate the Integrity of Structures
  1. Carry out inspections to identify damage. ...
  2. Check that a structure has been built according to the appropriate designs, procedures and standards.
  3. Check that a structure is being used appropriately for the environment designed for.

What is enclosure integrity test? ›

Enclosure integrity testing uses a blower door to measure the total leakage area of rooms protected by fire suppression systems. The measured leakage area from the blower door test can then be used to estimate retention times for various clean agent fire extinguishing systems installed in the protected room.

What is self sealability the QC test for? ›

Self Sealability:- This test is applicable to closures intended to be used with water close the vials with the 'Prepared' closures. For each closure, use a new hypodermic needle with an external diameter of 0.8 mm & pierce the closure 10 times, each time at a different site.

How is dye ingress test done? ›

For routine testing, the dye ingress method uses ten test samples and three positive controls. The samples are placed in a vacuum chamber with dye and either pressure or vacuum is applied to the samples. The positive controls are punctured with a microtube to allow dye into the vials.

What are the two types of integrity tests? ›

So as I said, there are two main types of integrity tests: covert (personality-based) tests that measure traits linked to rule adherence; and overt tests which assess an applicant's attitudes towards various counterproductive work behaviors (CWBs) directly.

What is the purpose of structural integrity test? ›

Structural Integrity Assessment is an approach to assess whether a structure is fit to withstand the service conditions safely and reliability throughout its predicted lifetime.

How do you test container closure integrity? ›

The Dye Ingress test is both a destructive and probabilistic method for measuring container closure integrity. For dye ingress, samples and positive controls are submerged into a dye bath. They are subjected to pressure cycles, and they are then visually evaluated or alternatively evaluated by spectrophotometry.

Which test is used to assess the integrity of the seal on a glass container? ›

All of these defects can be picked up by Container Closure Integrity Testing (CCIT) – an assay that evaluates the adequacy of container closure systems to maintain a sterile barrier against potential contaminants.

What is the difference between QC and testing? ›

QA, QC, and Testing are like a chain that works together to ensure a high-quality product. QA sets the standards for how it should be done, QC ensures those standards are followed, and Testing checks that everything is up to the quality standards.

When should QC testing be performed? ›

Every time you open a new container of test strips or a new vial of QC solutions. If the meter is dropped. If there is a question about a patient's glucose results (i.e., if the glucose result is inconsistent with clinical presentation) to ensure the meter is working properly.

What are the tests performed in QC? ›

Pharmaceutical Quality Control Testing
  • Counterion Analysis.
  • Volatile Organic Impurities and Residual Solvents.
  • Semi-Volatile Organic Impurities.
  • Non-Volatile Organic Impurities.
  • Extractables and Leachables.
  • Elemental Impurities.
  • Nitrosamine Impurity Analysis.
  • Method Life Cycle Management.

What is the methylene blue container closure integrity test? ›

During the test, the container closure test articles are put into an empty vacuum chamber to introduce negative pressure to the articles. This vacuum removes air inside the container/closure system. The vacuum is then released and methylene blue hydrate solution enters the chamber until it reaches atmospheric pressure.

Which dye is used in leak test? ›

It uses methylene blue dye or another colored chemical liquid to determine whether there is a leak or not. The test is done by placing the pack of blister into a container of vacuum leak detector which has been filled with methylene blue dye mixed with water.

What is the limit of dye ingress detection? ›

The US Food and Drug Administration (US FDA) effectively expects confirmation that dye ingress methods can detect leaks ≤20 µm (6).


1. PDA Europe - Container Closure Integrity Testing
(Parenteral Drug Association)
2. Intro of Container Closure Integrity Testing Company Zhongxun CCI testing
(Zillion CCIT)
3. Container Closure Integrity Testing (CCIT) (Analysis Make :Pressure/Vacuum Vessel)
4. Guidance for Understanding Container Closure Integrity Test Failures
(Nelson Labs)
5. Container Closure Integrity and Stability Testing for Rigid Containers
(Nelson Labs)
6. 1µm CCI Testing | Container Closure Integrity Testing | Vacuum Decay 1 micron | Sepha Multi-Q HD
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