(T1030-12-70) CSTD Force Testing Informs on Stopper Intrusion and the Force Users Must Overcome

Purpose: The use of Closed System Transfer Devices (CSTDs) is increasing globally to elicit protection to users handling hazardous drugs during dose preparation and administration. The USP < 800 > “Hazardous Drugs – Handling in Healthcare Settings” guidance became an informational chapter in December 2019 encouraging the use of CSTDs. CSTD users must use greater force to attach and pierce the stopper compared to a syringe and needle; in turn CSTDs and spikes have a higher risk of stopper intrusion. This work will enhance our understanding of stopper intrusion risk, distinguishing puncture vs intrusion force.

Methods: CSTD vial adaptors were used to 3D print Instron adaptors so that the force of CSTD vial adaptor attachment to a sealed vial (clamp force) could be quantified on an Instron 5942 with correlating video (Fig 1). The Bluehill 3 software was used to correlate the force profile with physical events recorded in the video, and to separate the CSTD clamp force on the vial from the CSTD spike force through the stopper (penetration force). CSTDs from three manufacturers, an adaptor spike, and blunt tip and beveled tip 18G needles were tested on 20 mm serum stoppers from four manufacturers and a 10R glass vial; and one CSTD was penetration force tested with 20 mm lyo stoppers from four manufacturers and a 10R glass vial. To determine if stoppers exhibiting higher penetration forces are at risk for stopper intrusion (push-in), we then determined the force required to push in a 20 mm stopper into a 10R glass vial. To measure push-in force, two blunt stainless steel intrusion rods were machined at 4 mm and 5 mm diameters based on the average and maximum CSTD spike diameters, respectively. The intrusion rods were attached to the Instron and used to push crimped stoppers into 10R glass vials. The intrusion rod was aligned on center or off center on 4 different serum stoppers; or on center, the front of the lyo stopper opening, or the back of the lyo stopper opening of 4 lyo stoppers.

Results: Penetration Force: The CSTD vial adaptor clamp force was always the maximum force in the overall profile and is the force that a user must overcome to attach the adaptor onto a vial. The penetration force varied across different CSTD vial adaptors from about 25 N to 110 N and was dependent on the stopper and spike design. The average penetration force of an 18G needle across all serum stoppers was only 7.9 N. Serum stopper A had the highest spike force regardless of device due to the stopper thickness and was significantly higher than the concave stoppers B, C, and D. For CSTD 2 and CSTD 3, the penetration force for stopper B was significantly different from stopper D. For the adaptor pike, stoppers B, C, and D were significantly different from each other. CSTD 2, which showed a high force with the serum stoppers, was selected to be tested with the 4 lyo stoppers. Lyo stoppers E and F showed penetration forces similarly to the concave serum stoppers B, C, and D, while lyo stoppers G and H were similar to the thick serum stopper A.

Intrusion Force: Majority of stoppers were pushed into the vial, however serum stopper C was punctured with both on center and off center orientations. Serum stopper B was punctured when tested on center, but only 10% of the time when tested off center. Lyo stopper H punctured 40% of the time when on center, and 10% of the time when toward the front lyo opening. The intrusion force ranged from as little as 50N for serum stopper D to 130N for lyo stopper H. The intrusion force was highly dependent on the stopper design and rubber formulation. The 4 lyo stoppers were very similar in design but differed in rubber formulation where we see intrusion forces of 60N vs 120N. Additionally, serum stoppers that tended to get punctured had higher off center forces where the septum is thicker to puncture whereas serum stoppers that tended to get pushed in had lower off center forces where the stopper was able to collapse closer to the edge (Fig 2).

Conclusion: One of the impacts of using CSTDs and adaptor spikes on stoppers is stopper intrusion. The risk of stopper intrusion may be evaluated by comparing the intrusion force compared to stopper puncture force. If the force required for CSTD spike penetration is equal to or greater than the intrusion force, then the stopper is at risk of stopper intrusion with that CSTD (Fig 3). We found stopper A and stopper D to be at higher risk of stopper intrusion due to the similar forces for puncture and intrusion.

References: 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 J Pharm Sci Technol. 2019 Jan-Feb;73(1):92-109. doi: 10.5731/pdajpst.2018.008664. Epub 2018 Sep 19. PMID: 30232140.

Acknowledgements: Affiliation:
1 Dosage Form Design & Development, BioPharmaceuticals Development, R&D, AstraZeneca, Gaithersburg, US
* Research conducted at AZ, author worked on project when employed at AZ
Disclosures:
* Current position at Abiomed