A Systematic Approach to Evaluating Closed System Drug-Transfer Devices During Drug Product Development

Abstract

The use of Closed System Drug-Transfer Devices (CSTDs) has increased significantly in recent years due to NIOSH and USP recommendations to use them during preparation of hazardous drugs. Mechanistic and material differences between CSTDs and traditional in-use components warrant an assessment of their impact on product quality and dosing accuracy. Using a combination of prevalent CSTDs with biologic molecules, we performed an extensive assessment of the effect of using CSTDs for dose preparation and observed no negative impact on product quality attributes. Additionally, we found that the CSTD hold-up volume is 2 to 4-fold higher than conventional in-use components and exhibited a strong dependence on the CSTD brand used. We also found that the CSTD brand and dosing volume have a major influence on dosing accuracy with suboptimal protein recovery at very low dosing volumes. We identified entrapment of product in the CSTD spike as the root cause for this sub-optimal recovery and found that flushing the CSTD spike with a brandnew syringe and not the dosing syringe aided in complete protein recovery. Taken together we present a systematic approach to evaluate the risks and impact of CSTD to drug product quality, dose preparation, and dosing accuracy.

Clinical Oncology Society of Australia Position Statement: 2022 update to the safe handling of monoclonal antibodies in healthcare settings

“…Institutions utilizing a CSTD should consider user experience and technique. They must also evaluate the device(s) to ensure that when correctly used, protein aggregation does not occur, the medication is compatible with the components of the CSTD 19,20,22 , and there are no significant small volume losses during the reconstitution process or administration 18,21 When preparations of mABs occur outside a centralized service as determined by institutional risk assessment, it should occur in a dedicated area away from patients and carers to minimize unnecessary exposure 1 …”

“…However, since the first COSA Position Statement, several consensus guidelines and position statements for the safe handling of mABs have been published, 3,6–8 as well as review papers 9,10,12 and commentary 11 on the occupational exposure risks. Among the relevant literature published since the 2013 Position Statement, literature relating specifically to pertuzumab, 13,14 closed system transfers devices (CSTDs) used with mABs, 3,18–22 a case report relating to staff sensitization to a mAB 5 , and the nomenclature change to mABs, 17 was identified.…”

“…In the last few years, there have been several papers published relating to the use of CSTDs in the preparation and administration of mABs 18–22 . While CSTDs provide enhanced protection against potentially hazardous exposures to healthcare workers, 3,13 performance standards for evaluation of CSTD containment are not yet available 23 .…”

“…Among the relevant literature published since the 2013 Position Statement, literature relating specifically to pertuzumab, 13,14 closed system transfers devices (CSTDs) used with mABs, 3,[18][19][20][21][22] a case report relating to staff sensitization to a mAB 5 , and the nomenclature change to mABs, 17 was identified.…”

“…23 Several publications on device performance have been published, with issues identified including vapor containment 19 and unintended volume loss associated with small-volume products. 18,21,22 Insoluble fine particles in the final product were detected when CSTDs were used in the preparation of mABs, but the clinical significance of this finding is uncertain. 20,21 Institutions should consider these potential issues when selecting CSTDs.…”