Industry guidance on container closure integrity strategies for difficult-to-test parenteral products (DTPs)

Innovative modalities, such as antibody-drug conjugates (ADCs), radiopharmaceuticals (RPhs), and cell and gene therapies (CGTs), along with ultrahigh-concentration monoclonal antibody suspensions or high-concentration parenteral products, present unique container closure integrity (CCI) challenges because of toxicity, biohazard or radioactivity, very small batch sizes, high cost, fragility, or requirements for ultralow (<-70 °C) and cryogenic (<-150 °C) storage. These "difficult-to-test" parenteral products (DTPs) demand a tailored, lifecycle-based CCI strategy. Industry experts propose a holistic approach that decouples CCI assurance from constraints imposed by scarce or hazardous drug product (DP) and by final-presentation testing limits. By leveraging surrogate-filled or empty container closure systems (CCSs), sensitive CCIT methods can be applied without consuming valuable DP, preserving safety, operational feasibility, and regulatory compliance across development and commercial stages. To illustrate the approach, we consider a representative DP case i.e., a small-volume (0.5 mL) aqueous gene-therapy example filled into 2 mL plastic vials with rubber closures and aluminum crimps, stored long-term at <-70 °C and produced in batches of ∼200-500 units. Additionally, key CCIT method considerations for DTPs are summarized.