COLD CHAIN
Digest Analysis
The recovery of the digestion/ analysis process was established by supplementing portions of the test sample with known amounts of the target elements prior to microwave digestion.
In this manuscript, we report the elemental entities profile of a plasticized poly-vinyl chloride (PVC) material which has historically been used in packaging systems for aqueous drug products. This profile, which establishes the total amount of elemental entities present in the PVC material, is used to determine the maximum daily dose of elemental impurities associated with a typical therapeutic situation. Such daily doses can be compared to relevant drug product Permissible Daily Exposures (PDEs) for elemental impurities to establish how much of the PDE is “used up” by packaging-related impurities. In the case of 2 of the predominant elemental entities, aluminum and zinc, the total pools of the elements in the material are compared to the amount that has been measured in solution products stored in PVC packaging.
Experimental
Test Article The test article consisted of sheets of plasticized PVC material. In addition to the PVC resin, primary and secondary plasticizers, and other additives, the PVC material was formulated to contain approximately 1250 ppm (mg/kg) of a mixed calcium/zinc stearate, used as an acid scavenger. Otherwise, the test article was not formulated to intentionally contain any other elemental entity.
Reagents
Acids used for digestion and standard preparation were J.T. Baker Ultrex II Ultrapure grade (
J.T.Baker, Center Valley, PA). The water
used in this study was obtained from a Milli-Q Purified Water generator (Millipore Corp., Billerica, MA).
Digestion (Total Pool)
Triplicate 0.5-g portions of the test article were digested using closed-vessel microwave- assisted strong acid digestion. This portion of the test article, along with 3 mL concentrated nitric acid and 1 mL water, was placed into quartz microwave digestion vessels (15-mL capacity). The quartz vessels were initially cleaned and were cleaned between uses by taking the vessels through the vendor’s recommended cleaning process. Digestion was performed with a Milestone (Shelton, CT) UltraWave Single reaction chamber microwave digestion system. The instrument was operated with a 3-step operating ramp: step 1 = 15-minute operating ramp (Temperature T1 = 120°C, Temperature T2 = 60°C), power = 800 watts, pressure = 160 bar; step 2 = 15-minute operating ramp (Temperature T1 = 220°C, Temperature T2 = 60°C), power = 1500 watts, pressure = 160 bar; step 3 = 5-minute operating ramp (Temperature T1 = 240°C, Temperature T2 = 60°C), power = 1500 watts, pressure = 160 bar. The digestion was performed at a pressure of approximately 50 bar. After the digestion was complete and the samples were cooled to ambient temperature, the contents of the digestion vessel (termed the digest) were transferred, with associated rinsing of the vessel, to a 100-mL volumetric flask, to which 2 mL of concentrated hydrochloric acid was added and which was subsequently diluted to the mark with water.
Pharmaceutical Outsourcing | 28 | March/April 2015
The digests were analyzed for 30 elements (Al, Sb, As, Ba, B, Cd, Co, Cr, Cu, Au, Ir, Fe, Pb, Li, Mn, Hg, Mo, Ni, Os, Pd, Pt, Rh, Ru, Se, Ag, Sn, Tl, W, V, and Zn) by inductively coupled plasma/mass spectrometry (ICP/MS) using 2 instrumental systems: Thermo (Waltham, MA) ThermoElemental X-Series 2 ICP/MS and Agilent (Santa Clara, CA) 7700x ICP/MS. The ThermoElemental X-Series 2 ICP/MS included an axial quartz torch (Catalog # 1281360), a Conikal glass expansion nebulizer (Catalog # AR-350-1-FC1E), and a quartz cyclonic spray chamber with a baffle and auxiliary gas port (Catalog # ES-3160-1111-23). The Agilent 770x ICP/MS included an axial quartz torch (Catalog # G3280-80053), a Micromist glass expansion nebulizer (catalog # ARG-1- UM04X), and a quartz spray chamber (Catalog # G3280-80008). In general, digests were analyzed using optimized conditions for both instruments. To optimize analytical performance for certain elements, Li and B were analyzed in the Standard Mode on the ThermoElemental instrument or the No Gas Mode on the Agilent instrument. The other elements were analyzed via the CCT Mode (7 % H2
, 93% He) on the ThermoElemental
instrument and the He Gas Mode (100% He) on the Agilent instrument. While multiple masses were monitored (when available) for each of the targeted elements, the data reported in this manuscript were obtained from the primary masses, thereby producing the greatest specificity and sensitivity.
Standards used to calibrate the ICP/MS systems were prepared by dilution of multi- element stock solutions obtained from High Purity Standards (Charleston, SC). The diluent was a mixture of 5% (v/v) nitric acid and 2% (v/v) hydrochloric acid. Multiple calibration standards were prepared at approximate concentrations of 0.1, 0.5, 1, 25, and 50 ng/mL (0.05, 0.1, 0.5, and 1 ng/mL for Hg).
In addition to the calibration standards, analytical performance throughout the analytical runs performed in this study was assessed, primarily with regard to response drift, via the sporadic analysis of quality control (QC) standards throughout the runs. These QC standards were prepared at concentrations comparable to the calibration standards but from stock solutions from an alternate vendor (Inorganic Ventures, Christiansburg, VA).
Analytical Recovery
The recovery of the digestion/analysis process was established by supplementing portions of the test sample with known amounts of the target elements prior to microwave digestion. Specifically, aliquots of standard mixtures were added to the acid and water solutions
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