Container Closure Integrity Test Using Frequency Modulation Spectroscopy Headspace Analysis with Carbon Dioxide as a Tracer Gas.

As described in USP <1207>, the container closure integrity (CCI) of a pharmaceutical package must be maintained throughout the product lifecycle to ensure sterility and stability. Current CCI test methods can be time-consuming, destructive, and lack the required sensitivity. This study presents a novel, fast, and nondestructive method for CCI testing that uses carbon dioxide as a tracer gas under effusive pressure conditions. Two types of defects were tested: laser-drilled defects located in the glass body (2, 5, and 10 µm nominal diameter) and tungsten wires inserted between the stopper and the landing seal of the vial (41, 64, and 80 µm outer diameter). During each test session, vials were placed in a pressure vessel, isolated from ambient conditions, and pressure-cycled by first pulling a vacuum and then applying an overpressure of pure carbon dioxide gas. After being exposed to 20 psig (34.7 psia) of carbon dioxide for 30 min, the overpressure was released and the vials were measured on an FMS-Carbon Dioxide Headspace Analyzer. This headspace gas analyzer utilizes a tunable diode laser absorption spectroscopy technique that employs frequency modulation to enhance measurement sensitivity. An increase of ≥1 torr in the headspace carbon dioxide content after completion of the pressure cycling procedure was intended to serve as confirmation of leak detection. All empty vials with either a 2 µm laser-drilled defect or 41 µm wire (effective defect size ∼2 µm), or greater, at the stopper-seal interface were detected by this method. Furthermore, vials filled with 1 mg/mL bovine serum albumin in phosphate-buffered saline containing a 5 µm laser-drilled defect below the liquid level or a 64 µm wire (effective defect size ∼6.1 µm), or greater, at the stopper-seal interface (defect above the liquid level) were detected. This test can be used for a wide variety of vial types and headspace compositions.

Method Development for Container Closure Integrity Evaluation via Headspace Gas Ingress by Using Frequency Modulation Spectroscopy.

USP <1207.1> Section 3.5 states that "A deterministic leak test method having the ability to detect leaks at the product's maximum allowable leakage limit is preferred when establishing the inherent integrity of a container-closure system." Ideally, container closure integrity of parenteral packaging would be evaluated by measuring a physical property that is sensitive to the presence of any package defect that breaches package integrity by increasing its leakage above its maximum allowable leakage limit. The primary goals of the work presented herein were to demonstrate the viability of the nondestructive, deterministic method known as laser-based gas headspace analysis for evaluating container closure integrity and to provide a physical model for predicting leak rates for a variety of container volumes, headspace conditions, and defect sizes. The results demonstrate that laser-based headspace analysis provides sensitive, accurate, and reproducible measurements of the gas ingress into glass vial-stopper package assemblies that are under either diffusive or effusive leak conditions. Two different types of positive controls were examined. First, laser-drilled micro-holes in thin metal disks that were crimped on top of 15R glass vials served as positive controls with a well-characterized defect geometry. For these, a strong correlation was observed between the measured ingress parameter and the size of the defect for both diffusive and effusive conditions. Second, laser-drilled holes in the wall of glass vials served as controls that more closely simulate real-world defects. Due to their complex defect geometries, their diffusive and effusive ingress parameters did not necessarily correlate; this is an important observation that has significant implications for standardizing the characterization of container defects. Regardless, laser-based headspace analysis could readily differentiate positive and negative controls for all leak conditions, and the results provide a guide for method development of container closure integrity tests.LAY ABSTRACT: The new USP 39 <1207>, "Package Integrity Evaluation-Sterile Products", states in section 3.4.1: "tracer gas tests performed using … laser-based gas headspace analysis [have] been shown to be sensitive enough to quantitatively analyze leakage through the smallest leak paths found to pose the smallest chance of liquid leakage or microbial ingress in rigid packaging." In addition, USP <1207> also states that "for such methods, the limit of detection can be mathematically predicted on the basis of gas flow kinetics." Using the above statements as a foundation, this paper presents a theoretical basis for predicting the gas ingress through well-defined defects in product vials sealed under a variety of headspace conditions. These calculated predictions were experimentally validated by comparing them to measurements of changes in the headspace oxygen content or total pressure for several different positive controls using laser-based headspace analysis. The results demonstrated that laser-based headspace analysis can, by readily differentiating between negative controls and positive controls with a range of defect sizes on the micron scale, be used to assess container closure integrity. The work also demontrated that caution must be used when attempting to correlate a leak rate to an idealized defect-size parameter.

Healthcare system resiliency: The case for taking disaster plans further - Part 2.

For the most part, top management is aware of the costs of healthcare downtime. They recognise that minimising downtime while fulfilling risk management standards, namely, 'duty of care' and 'standard of care', are among the most difficult challenges they face, especially when coupled with the increasing pressure for continued service availability with the frequency of incidents. Through continuous operational availability and greater resiliency demands a new, combined approach has emerged, which necessitates that the disciplines of: (1) enterprise risk management; (2) emergency response planning; (3) business continuity management including IT disaster recovery; (4) crisis communications be addressed with strategies and techniques designed and integrated into a singular, seamless approach. It is no longer feasible to separate these disciplines. By integrating them as the gateway for service continuity, the organisation can enhance its ability to run as a business by helping to identify risks and prepare for change, prioritise work efforts, flag problems and pinpoint important areas that underpin the overarching business continuity processes. The driver of change in staying ahead of the risk curve, and the entry point of a true resiliency strategy, begins with identifying the synergies of the aforementioned disciplines and integrating each of them to jointly contribute to service continuance.

Healthcare system resiliency: The case for taking disaster plans further--Part 1.

To establish true healthcare resiliency, and to better position healthcare organisations to provide effective response, continuity, resumption and recovery of fundamental services and operations during serious incidents and disasters, the disaster planning process must evolve into an integrated approach of four contingency planning disciplines that holistically examine the end-to-end, all-hazard response continuum. This process also needs to incorporate and scale multifarious organisational levels and, when required, the health sector. This paper is the first component of two independent, but related, pieces. It will examine the typical state of disaster preparedness and plans in healthcare, examine the worth and value of honing disaster plans, and will introduce two recommended contingency planning disciplines: enterprise risk management and emergency response planning. For each discipline, a case will be made for its inclusion into the overall disaster planning process, including examination of background information, benefits, how it improves disaster planning, and other resources helpful to the reader. The second paper, in afuture issue of the Journal of Business Continuity & Emergency Planning, will introduce business continuity management--including IT disaster recovery--and crisis communications as the third and fourth contingency planning disciplines needed for a fully integrated approach. The opinions expressed in this paper are those of the authors and may not be entirely those of the organisation.

Quantum dissociation of an edge of a Luttinger liquid.

In a Luttinger liquid phase of one-dimensional molecular matter the strength of zero-point motion can be characterized by dimensionless De Boer's number quantifying the interplay of quantum fluctuations and two-body interactions. Selecting the latter in the Morse form we show that dissociation of the Luttinger liquid is a process initiated at the system edge. The latter becomes unstable against quantum fluctuations at a value of De Boer's number which is smaller than that of the bulk instability which parallels the classical phenomenon of surface melting.