(T1030-02-09) Understanding the Compatibility of CSTDs with Container Closure Systems in Accordance with USP < 382 > to Meet Functionality Requirements

Purpose: Closed System Drug-Transfer Devices (CSTDs) are designed to allow hazardous drugs to transfer from a vial to a syringe in a controlled and sealed environment. (1) As United States Pharmacopeia (USP) 382 “Elastomeric Component Functional Suitability in Parenteral Product Packaging/Delivery Systems” is planned to become effective December 2025, there is a need to understand and apply the new requirements alongside existing requirements from USP 697 “Container Content for Injections.” The purpose of this study was to understand the performance of serum and lyophilization stoppers with three distinct industry CSTDs on both glass and cyclic olefin polymer (COP) 10 mL vials. The serum and lyophilization stoppers will be evaluated for fragmentation, penetration force, spike retention, sealability capacity, and residual volume in the system to demonstrate their compliance with USP 382 and 697.

Methods: Three commercially available CSTDs were tested with varying configurations of both glass and cyclic olefin polymer (COP) 10 mL vials and single-formulation 20 mm stoppers in both lyophilized and serum vial configurations. One CSTD selected has two unique configurations and each was tested, differentiating the two configurations in the results with CSTD 2-A and CSTD 2-B. Fragmentation testing, penetration force testing, and spike retention and sealability testing were performed per USP 382. Residual volume was measured per USP 697. Fragmentation testing evaluated 10 container systems for the propensity of the spike to create a fragment as it is inserted through the elastomeric stopper. The packaging/delivery system is found to be acceptable if Not More Than (NMT) 20 elastomeric closure particles ≥150μm in any dimension are observed per 10 samples tested. Penetration force testing was performed to measure the force required to penetrate a stopper with the spike to determine the ease of use of the stopper as well as the ability of the system to avoid stopper intrusion. (2) The key USP 382 acceptability criterion is the force must not exceed 80 Newtons (N), and the overall sample average is less than 75 N. Spike retention and sealability evaluates the performance of the elastomeric stopper when penetrated by a spike, measuring the stopper’s ability to seal around that spike. For the system to be acceptable, the closure must be penetrated fully without pushing the closure into the vial, the spikes are retained in the closures for the test period, and no liquid leakage is observed. Residual volume was measured to verify there is sufficient liquid in the vial to allow for withdrawal of the labeled volume. A total of five samples were tested for each CSTD combination.

Results: Overall testing results are summarized in Table 1, providing an overview of data outcomes from testing penetration force, fragmentation, spike retention and sealability, and residual injection volume. The performance of each CSTD-closure configuration for penetration force testing is observable in Figure 1. The evaluation of penetration force produced results with CSTD 1 performing the highest insertion forces in both glass and COP systems. Further, this device exceeded the USP recommended insertion force for both the lyophilization and serum stoppers. CSTD 2-A showed the lowest insertion forces in both glass and COP systems. This device would meet the USP recommended insertion force for both the lyophilization and serum stoppers. CSTD 3 and CSTD 2-B were comparable and showed insertion forces at or above the USP recommended specifications. Fragmentation testing resulted in data showing that fragments were seen only in the lyophilization stoppers, regardless of vial type, except for the lyophilization stopper on glass with the CSTD 1 configuration. No CSTDs exhibited any fragments ≥150μm for the serum stoppers. The testing of spike retention and sealability resulted in no observations of the sample configurations showing signs of leakage or becoming dislodged during the testing. Stopper intrusion was not observed and all CSTDs penetrated the stoppers under test. Injection volume testing was successfully performed on CSTDs with injection volumes less than 10 mL with four of the serum and one of the lyophilization stoppers. Four of those systems differed by a small amount of 0.01 mL. CSTD 1 assembled on a glass vial with the serum stopper showed the largest discrepancy with over 1.6 mL loss. This was likely due to liquid becoming trapped in the housing of the CSTD, which is a well-documented failure mode of this device associated with user error, as denoted in the Food and Drug Association’s Manufacturer and User Facility Device Experience.

Conclusion: All of the CSTD-closure combinations demonstrated testing outcomes adhering to performance testing guidelines from USP 382 and 697. The performance of commercially available CSTDs validates the usage of these devices with glass and COP vials in tandem use with lyophilization and serum stoppers. The data from this study additionally demonstrates the readiness of the commercial CSTD and component markets for the official implementation of USP 382, anticipated December 2025.

References: 1. Patke S, Gaillat EN, Calero-Rubio C, Gooding TB, Audat H, Leman M, et al. A Systematic Approach to Evaluating Closed System Drug-Transfer Devices During Drug Product Development. Journal of Pharmaceutical Sciences [Internet]. 2022 May 1 [cited 2022 Jul 19];111(5):1325–34.
2. Zhao XC, Ho L, Bantz D, Hostetler D, Fang L. A Case Study to Address a Gap in the Device-to-Vial Interface Stopper Push-in by Chemo Spikes. PDA journal of pharmaceutical science and technology [Internet]. 2019 [cited 2023 Apr 27];73(1):92–109.

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Table 1. Summary of functionality requirement testing for CSTDs with varying combinations of stoppers and vials.


Figure 1. Bar chart visualizing the mean penetration force with error bars for each CSTD-closure configuration, (N=10 per sample).