Container closure integrity (CCI) is a critical element of sterile product quality, but evaluating a CDMO’s CCI capabilities requires more than confirming that testing is available.
The appropriate approach depends on the drug product, container closure system, manufacturing process, lifecycle risks, and applicable regulatory requirements. For pharmaceutical companies selecting or qualifying a CDMO, understanding how a manufacturing partner approaches these variables can provide useful insight into the maturity of its overall quality program.
Oliver Stauffer, CEO of PTI (Packaging Technologies and Inspection), has more than two decades of experience in container closure integrity testing and quality risk assessment. In a recent PharmaSource podcast, he discussed several considerations for assessing CCI strategies across vials, prefilled syringes, autoinjectors, and other sterile product formats.
The discussion points to six areas sponsors should consider when evaluating a CDMO’s approach to container closure integrity.
1. CCI Specifications Should be Based on Product Risk
Container closure integrity is sometimes approached as a binary question: does the package leak or not?
Oliver argues that a more useful starting point is understanding the degree of leakage that could present a meaningful risk to the specific product.
“Everything leaks. Now we need to understand to what extent it can leak, or to what level of risk we can take on.”
The relevant acceptance criteria therefore depend on the product and its vulnerabilities. Moisture ingress, oxygen exposure, microbial ingress, and other factors may have different implications depending on the formulation and container closure system.
Rather than beginning with an arbitrary defect size or instrument sensitivity, manufacturers should first establish what constitutes a meaningful risk to product quality and patient safety. That assessment can then inform the required sensitivity and appropriate CCI methodology.
For sponsors evaluating CDMOs, an important question is therefore not simply whether a CDMO performs CCIT, but how it establishes appropriate acceptance criteria for a specific product.
2. CCI Should be Supported by a Documented Quality Risk Assessment
“Quality risk management is something that defines just about every decision that is made within the pharmaceutical industry. Everything is a risk-based decision.”
CCI cannot be evaluated independently of the broader product and manufacturing process.
Oliver describes quality risk assessment as a multidisciplinary exercise incorporating the physicochemical characteristics of the drug product, microbiological risks, material science, container design, closure mechanisms, and manufacturing conditions.
This assessment should also consider the complete product lifecycle. Container and closure performance at initial production may not fully represent performance after transportation, storage, aging, or other stresses.
ICH Q8 and ICH Q9 provide an important framework for this approach through quality by design and quality risk management principles.
When assessing a CDMO, sponsors should understand how CCI is incorporated into the manufacturer’s broader risk-management framework. A mature program should be able to explain the relationship between product characteristics, package design, process parameters, identified failure modes, and the selected test method.
3. Test Methodology is an Important Indicator of CCI Program Maturity
The test methods used by a CDMO can provide insight into the maturity of its container closure integrity strategy.
Oliver recommends that sponsors examine whether a CDMO continues to rely on probabilistic methods such as dye ingress or has adopted deterministic CCI technologies where appropriate.
“If a CDMO is still driving forward with a dye ingress test method, I think that should immediately initiate some pause, and you should start asking questions a little bit about their container closure program.”
The issue is broader than the presence of a particular instrument or test. Sponsors should understand how the CDMO selected and validated its methodology, what level of sensitivity it can reliably achieve, and how the method relates to identified product risks.
Deterministic methods can also provide advantages beyond regulatory compliance. Depending on the application, they can support greater repeatability, quantitative measurement, and process understanding.
“More and more CDMOs are moving to a deterministic platform and are able to actually show that as a real position of strength.”
During CDMO due diligence, sponsors should therefore examine the scientific rationale behind the CCI methodology rather than treating CCIT capability as a simple yes-or-no qualification criterion.
4. Regulatory Requirements are Increasing Expectations for Scientifically Justified CCI Strategies
Current regulatory expectations reinforce the move toward risk-based and scientifically justified container closure integrity programs.
EU GMP Annex 1 establishes specific expectations for integrity testing of sterile product containers, including requirements affecting certain fused containers and small-volume parenteral formats. USP <1207> also provides a framework for package integrity evaluation and the selection of appropriate test methods.
“We’ve seen that Annex 1… is a product ultimately of all the regulatory bodies coming together.”
For sponsors, regulatory compliance is only one part of the assessment. It is also important to understand how a CDMO interprets these requirements and incorporates them into its control strategy.
“Once you have a test system in place, you must make sure that you are applying the right control strategy to assure that you’re managing risk effectively.”
Oliver notes that some regulatory requirements are necessarily broad and may not reflect the exact risk profile of every product or package configuration. This makes the underlying quality risk assessment particularly important.
A capable CDMO should be able to explain both what testing it performs and the scientific and regulatory rationale for that approach.
5. Prefilled Syringes and Autoinjectors Introduce Additional Integrity Considerations
Combination products and self-administered injectable formats can introduce additional CCI complexity.
A vial typically has a relatively limited number of closure interfaces. Prefilled syringes contain multiple potential integrity points, while autoinjectors add further assembly steps and components around the primary container.
Each additional interface or manufacturing step can introduce potential failure modes that need to be considered within the overall control strategy.
As Oliver explains:
“Once you go to a prefilled syringe, now you have multiple closure points and multiple opportunities for risk.”
Testing can also become more difficult once the primary container is incorporated into a fully assembled device. Not every CCI technology is suitable for evaluating an assembled autoinjector, which makes test-method selection and development an important consideration during device and manufacturing planning.
Sponsors transferring prefilled syringe or autoinjector products should therefore evaluate whether the CDMO has relevant experience with the specific container and device configuration, rather than relying solely on general fill-finish experience.
6. CCI Capability Should be Evaluated During CDMO Due Diligence
CCI is most effective when considered early in product and manufacturing strategy rather than addressed only during validation or in response to a deviation.
For sponsors evaluating a CDMO, due diligence should include questions about how the manufacturer develops, validates, and maintains its CCI program.
Relevant areas to examine include:
- How does the CDMO conduct CCI quality risk assessments?
- How are critical product characteristics incorporated into test-method selection?
- Which deterministic and probabilistic technologies are available?
- How are acceptance criteria and required sensitivity established?
- How is the method validated for the specific container closure system?
- How are lifecycle factors such as aging, transportation, and storage considered?
- How is CCI monitored as manufacturing processes or components change?
- What experience does the CDMO have with the sponsor’s specific container or device format?
The same principle applies when selecting a specialist CCI provider. Technology selection should follow an assessment of the drug product, package, manufacturing process, and patient risks rather than precede it.
As Oliver explains:
“The product itself that goes inside the container often is the most critical aspect to selecting the right container closure integrity test system.”
CCI as part of CDMO selection
For pharmaceutical companies outsourcing sterile manufacturing, container closure integrity should form part of the technical and quality assessment of prospective CDMO partners.
The objective is not simply to confirm that a manufacturer can perform a CCI test. Sponsors should determine whether the CDMO can establish a scientifically justified strategy that connects product risk, container closure design, manufacturing controls, test methodology, validation, and lifecycle management.
That distinction becomes increasingly important as sterile products move toward more complex delivery formats such as prefilled syringes and autoinjectors.
A CDMO with a mature CCI program should be able to explain not only how it tests container closure integrity, but why its approach is appropriate for the specific product and package.
