Due to the overwhelming number of abstracts received, this year's PDA Parenteral Packaging conference featured two sessions on closed system transfer devices (CSTDs). Four experts offered their take on this critical topic:
- Cathy Zhao, West Pharmaceutical Services, “Development of Guidance for the Interconnectibility between Vial Container Closure Systems and Vial Transfer Devices” [Author’s Note: Zhao’s article on closed system transfer devices can be read here.]
- Kunjal Oza, Genentech/Roche, “Considerations for Using Closed System Transfer Devices with Biological Drug Products”
- Katharina Golly, Novartis, “CSTDs: How to Apply USP in Combination Product Development”
- Holger Roehl, F. Hoffmann-La Roche, “CSTD Selection for an Established Container Closure System - A Case Study”
From the presentations and subsequent Q&A, it was clear that many pharmaceutical companies are struggling with similar issues resulting primarily from a lack of standardization among CSTDs available on the market. A visual comparison makes this obvious—no standard shape or dimensions, not even a standard construction material for the fluid path. CSTDs can be made of polypropylene, polytetrafluoroethylene, stainless steel, acrylonitrile butadiene styrene, polyvinyl chloride, polycarbonate, silicone, thermoplastic elastomers, or polyisoprene, to name a few. The variety of parameters for these devices necessitates they be handled differently, not to mention the diverse selection of the requisite counterparts—stoppers and vials.
Hospital contracts with specific device suppliers and administrative procedures often locks institutions into using a specific manufacturer’s device, even if the device does not properly fit a wide variety of drug container closure systems. This can create drug product handling issues, like broken vials due to the excessive forces that may be applied to pierce the CSTD spike through a stopper. High puncture forces may also push the stopper into the vial, as presented at the 2018 PDA Parenteral Packaging Conference. These container closure failures represent obvious challenges. Less obvious, but of equal concern, is a topic addressed repeatedly in PDA presentations— the significant number of both subvisible and visible particles generated during CSTD use. Most particles found were silicone, but some resulted from the manufacturing material of the device, the rubber stopper or even aggregated proteins. Studies also confirmed how differently these diverse CSTDs performed; while some had a very low count, others generated thousands of particles.
One concern raised by the PDA audience was CSTDs being used to extend the use of vials that do not contain antimicrobial preservatives for medicines. Not only is this off-label use of CSTDs not qualified for this procedure, but it raises the potential of creating a dangerous situation should a breach in sterility not be detected before the drug is administered to a patient. To be fair to CTSDs, they were initially intended to protect the user from the hazardous drug inside the vial. They were not designed to maintain sterility without preservatives, nor were they historically tested for chemical compatibility or particle generation.
Concerning standardization, participants agreed that the Product Quality Research Institute (PQRI) project, in which PDA is also involved, is a first step in the right direction. The broad scope of the project covers general vial transfer systems and the interconnectability of vial container closure systems and vial transfer devices. Many key stakeholders are working together on developing and promoting best practices and a guidance for CSTDs. This guidance would include relevant quality and performance requirements.
As the development of biological drugs evolve, use of these sophisticated molecules carries a high price. Drug companies do not want to lose the molecules through interactions with a device. As reported by all conference presenters, the impact of drug holdup volume is of particular concern, as it can result in drug loss and improper dosing.
Another issue that raised much discussion among participants is chemical compatibility with the device. According to USP General Chapter <800>, CSTDs should only be used if they are compatible with the drug. Yet a Genentech-sponsored survey found that only 50% of hospitals reach out to device manufacturers for compatibility data.
That, in turn, leaves behind many unanswered questions: How is compatibility defined? What are measurable criteria? And, how are extractables and leachables accounted for? The survey showed that hospitals in every country, and some within individual countries, are dealing with this challenge differently. The U.S. National Institute of Occupational Safety and Health (NIOSH) publishes a list of hazardous drugs; however, the Genentech survey showed that not all hospitals or all countries, use it. In fact, some hospitals create their own lists.
Clearly, common global standards and guidances for CSTDs are needed but lacking.
Some pharmaceutical companies already include CSTDs in their product development. This provides greater confidence in a successful preparation and treatment. But with that comes additional responsibility for the pharmaceutical company in the form of a greater regulatory burden, as drug and device require co-packaging and a more stringent regulatory process. This scenario, though, often causes frustration for pharmaceutical companies when they see some hospitals discarding the co-packaged device and using their own, instead, one that might be less suited in a specific case.
This last point instigated a very lively discussion that resolved in agreement—the flow of information and education must be increased significantly. Hospital personnel would benefit from more in-person, on-site training to facilitate an understanding of the implications and consequences of improper CSTD usage. On the other hand, handling of CSTDs needs to be facilitated to support caregivers in their time-critical occupation.
By the end of the two sessions, one thing was very clear: CSTDs are a hot topic that warrants a follow-up session at next year’s PDA Parenteral Packaging Conference. Join this important discussion at the 2021 conference next March and help shape the future of parenteral packaging.