Long-Term Study of Container Closure Integrity of Rubber-Glass Vial Systems by Multiple Methods.

A one-year study to establish the container closure integrity (CCI) performance landscape of systems comprising rubber stoppers and glass vials was performed. Focus was on addressing the issues of CCI performance versus: (a) time, (b) compression levels and residual seal force (RSF) values, and (c) potential variation in results based upon the deterministic measurement method (tracer gas and frequency modulated spectroscopy). To reduce sample size to a manageable number, the study was based upon a design of experiments that considered a range of: (a) stopper formulations, sizes, and configurations; (b) vial sizes, types, and suppliers; and (c) compression levels. All systems showed good performance; there was no decrease in CCI with time, highlighting the general robustness of rubber-glass vial systems. Lower compression/RSF values tended to give slightly lower performance and wider scatter in data and thus should not be recommended for commercial applications. A small amount of oxygen exchange through the stoppers was observed for all systems-to be expected because rubber is known to be gas permeable. Consistent with models, RSF values decreased initially and then remained constant. Results are consistent with the literature.

How to Qualify Container Closure Systems for Intended Use, Part 1.

The U.S. Food and Drug Administration regulates outsourcing facilities with the same stringency they apply towards drug manufacturers. This means that outsourcing facilities, who must navigate the changing regulatory landscape to achieve and maintain 503B status, need to focus on qualifying container closure systems for their intended use. Container closure systems must be fit-for-purpose (i.e., suitable for in-use conditions relative to drug product stability over intended shelf-life and storage conditions). This article, the first of a two-part series, addresses the critical aspect of how to qualify systems for intended use regarding container closure integrity. The second part will address component selection.

Mitoxantrone targets human ubiquitin-specific peptidase 11 (USP11) and is a potent inhibitor of pancreatic cancer cell survival.

UNLABELLED: Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer-related death in the United States, with a 95% five-year mortality rate. For over a decade, gemcitabine (GEM) has been the established first-line treatment for this disease despite suboptimal response rates. The development of PARP inhibitors that target the DNA damage repair (DDR) system in PDA cells has generated encouraging results. Ubiquitin-specific peptidase 11 (USP11), an enzyme that interacts with the DDR protein BRCA2, was recently discovered to play a key role in DNA double-strand break repair and may be a novel therapeutic target. A systematic high-throughput approach was used to biochemically screen 2,000 U.S. Food and Drug Administration (FDA)-approved compounds for inhibition of USP11 enzymatic activity. Six pharmacologically active small molecules that inhibit USP11 enzymatic activity were identified. An in vitro drug sensitivity assay demonstrated that one of these USP11 inhibitors, mitoxantrone, impacted PDA cell survival with an IC50 of less than 10 nM. Importantly, across six different PDA cell lines, two with defects in the Fanconi anemia/BRCA2 pathway (Hs766T and Capan-1), mitoxantrone is 40- to 20,000-fold more potent than GEM, with increased endogenous USP11 mRNA levels associated with increased sensitivity to mitoxantrone. Interestingly, USP11 silencing in PDA cells also enhanced sensitivity to GEM. These findings establish a preclinical model for the rapid discovery of FDA-approved compounds and identify USP11 as a target of mitoxantrone in PDA. IMPLICATIONS: This high-throughput approach provides a strong rationale to study mitoxantrone in an early-phase clinical setting for the treatment of PDA.