Ensuring container closure integrity (CCI) is a foundational requirement in pharmaceutical manufacturing. Whether developing sterile injectables, biologics, or combination products, the ability to maintain a sterile barrier throughout the product lifecycle is directly tied to patient safety, product efficacy, and regulatory compliance.
Choosing the right CCIT method is not a one-size-fits-all decision. It requires a clear understanding of the container system, critical quality attributes, and critical material attributes along with knowledge of benefits and limitations of each available technology.
Understanding your Product – Package
A successful CCI strategy starts with a thorough understanding of your product-package configuration. Each product-package has its own unique requirements for maintaining sterility, formulation, stability, headspace, and/or other package specific requirements. Understanding the level of allowed leakage, or the maximum allowable leakage limit (MALL) is paramount. These are impacted by the formulation, materials, and selected closure system.
Container Closure System
Whether the container system is a vial, syringe, cartridge, BFS card, etc. each presents different points of concern to assess and safeguard. Not only must each closure be effective in preventing egress of the formulation and often administering the dosage, but it must also support the maintenance of each Critical Quality Attribute of the product. Critical Quality Attributes (CQA), being the properties required to protect product stability. The sensitivity required to maintain CQA’s, the shape of the package, and the closure type all influence test method selection.
Material Considerations
Within the Container Closure System, there are a variety of materials used to support container integrity. Each material has its own limitations which must be assessed at each stage of the product lifecycle. Materials have their own Critical Material Attributes (CMAs) which influence closure system selection, sterilization methods, transport, and storage.
For example, septums and plungers must remain elastomeric in order to provide a proper interference seal and maintain integrity. However, when subjected to temperatures below its glass transition temperature, elastomers shrink and become brittle, potentially comprising integrity. This narrows in the available test methods to only those capable of inspecting temperatures outside of ambient. Based on storage requirements, permeability, and material composition, test methodology may differ.
Formulation
Product formulation is one of the largest influences in test method selection. Conventional Pharmaceuticals, ATMP’s, and Biologics all have drastically different profiles from viscosity to molecule size, conductivity, and state of matter. Each of these characteristics often limit the type of technology utilized.
For instance, pressure differential-based technologies such as vacuum decay, dye ingress, headspace analysis*, and mass extraction, all struggle with inspecting large molecule and viscous products. Larger molecules can clog defect sites and prevent detection causing false readings. Technologies such as MicroCurrent HVLD have the ability to detect any defect which has a liquid path, making it the most suitable technology for larger molecule formulations.
Where to Begin
Test method selection may seem complex with a multitude of factors influencing selection however there are a few key questions to ask.
- What is the container type?
- What are the primary functions of the container? Is it to:
- Maintain headspace
- What are the primary functions of the container?
- Safeguard sterility
- Maintain stability
- Prevent product egress
- Act as the method of administration (PFS, Combination devices)
- Is the formulation solid or liquid?
- What are the storage conditions?
Conclusion
Understanding the characteristics of your product-package and the benefits and limitations of each technology enables organizations to select the most effective technology or series of technologies to deploy for their CCI program. Every aspect of development, manufacturing, and shelf-life impacts the test methodology selected.