Integrity performance assessment of a closed system transfer device syringe adaptor lock as a terminal closure for Luer-Lock syringes.

OBJECTIVES: To investigate the container closure integrity of a closed system transfer device syringe adaptor lock in combination with disposable Luer-Lock syringes as the terminal closure device. The UK National Health Service (NHS) Pharmaceutical Quality Assurance Committee (PQAC) requires syringe integrity data for final storage devices of aseptic products such as chemotherapy drugs when prepared in advance and stored before use, as is standard practice for dose banded drugs. The assessment comprised both physical and microbial integrity testing of the combination closed system/Luer-Lock syringe containers at syringe sizes of 1 mL, 20 mL, and 50 mL. METHODS: Integrity testing was performed as described in the NHS Pharmaceutical Quality Assurance Committee yellow cover document, second edition 2013 'Protocols for the Integrity Testing of Syringes', with Chemfort (Simplivia, IL) syringe adaptor lock (SAL) devices as replacement for sterile blind hubs. Microbiological integrity was assessed according to method 1 part 1.4 using Brevundimonas diminuta at 32°C for up to 14 days of contact time. Two positive control devices per syringe size were tested using a blind hub cap as closure which was loosened before the test. Physical integrity was assessed using method 3 of the yellow cover document which is a dye intrusion method. Dye intrusion was assessed both visually and using a validated ultraviolet-visible spectrophotometer method. For each size/batch of test articles a positive control device (n=1) was assessed using a wire wrapped around the syringe plunger tip deliberately compromising integrity. Negative controls for each size (n=1) consisted of devices not immersed in methylene blue dye. RESULTS: Chemfort syringe adaptor lock/Luer-Lock syringe combinations were shown to be: (1) free of microbiological contamination after 14 days of contact time (n=60); and (2) free of dye intrusion at all syringe sizes tested (n=61 in total). The data demonstrate 100% closure integrity of the final container system when the Chemfort syringe adaptor lock replaces the syringe hub as the terminal closure device. All positive control devices demonstrated system suitability as container integrity was compromised in all positive control tests. All negative controls were negative for microbial and dye intrusion. CONCLUSIONS: Syringe adaptor lock components complied with the NHS Pharmaceutical Quality Assurance Committee yellow cover document syringe integrity requirements when used as the terminal closure of Luer-Lock disposable syringes from 1 mL up to 50 mL. Therefore, syringe adaptor lock (Chemfort) can be used as the terminal closure system for pre-filled syringes of chemotherapeutic drug products prepared in advance in UK NHS pharmacy technical services.

Stop-Frame Filming and Discovery of Reactions at the Single-Molecule Level by Transmission Electron Microscopy.

We report an approach, named chemTEM, to follow chemical transformations at the single-molecule level with the electron beam of a transmission electron microscope (TEM) applied as both a tunable source of energy and a sub-angstrom imaging probe. Deposited on graphene, disk-shaped perchlorocoronene molecules are precluded from intermolecular interactions. This allows monomolecular transformations to be studied at the single-molecule level in real time and reveals chlorine elimination and reactive aryne formation as a key initial stage of multistep reactions initiated by the 80 keV e-beam. Under the same conditions, perchlorocoronene confined within a nanotube cavity, where the molecules are situated in very close proximity to each other, enables imaging of intermolecular reactions, starting with the Diels-Alder cycloaddition of a generated aryne, followed by rearrangement of the angular adduct to a planar polyaromatic structure and the formation of a perchlorinated zigzag nanoribbon of graphene as the final product. ChemTEM enables the entire process of polycondensation, including the formation of metastable intermediates, to be captured in a one-shot "movie". A molecule with a similar size and shape but with a different chemical composition, octathio[8]circulene, under the same conditions undergoes another type of polycondensation via thiyl biradical generation and subsequent reaction leading to polythiophene nanoribbons with irregular edges incorporating bridging sulfur atoms. Graphene or carbon nanotubes supporting the individual molecules during chemTEM studies ensure that the elastic interactions of the molecules with the e-beam are the dominant forces that initiate and drive the reactions we image. Our ab initio DFT calculations explicitly incorporating the e-beam in the theoretical model correlate with the chemTEM observations and give a mechanism for direct control not only of the type of the reaction but also of the reaction rate. Selection of the appropriate e-beam energy and control of the dose rate in chemTEM enabled imaging of reactions on a time frame commensurate with TEM image capture rates, revealing atomistic mechanisms of previously unknown processes.