A Compilation of Metals and Trace Elements Extracted from Materials Relevant to Pharmaceutical Applications such as Packaging Systems and Devices.

Nearly 100 individual test articles, representative of materials used in pharmaceutical applications such as packaging and devices, were extracted under exaggerated conditions and the levels of 32 metals and trace elements (Ag, Al, As, B, Ba, Be, Bi, Ca, Cd, Co, Cr, Cu, Fe, Ge, Li, Mg, Mn, Mo, Na, Ni, P, Pb, S, Sb, Se, Si, Sn, Sr, Ti, V, Zn, and Zr) were measured in the extracts. The extracting solvents included aqueous mixtures at low and high pH and an organic solvent mixture (40/60 ethanol water). The sealed vessel extractions were performed by placing an appropriate portion of the test articles and an appropriate volume of extracting solution in inert extraction vessels and exposing the extraction units (and associated extraction blanks) to defined conditions of temperature and duration. The levels of extracted target elements were measured by inductively coupled plasma atomic emission spectroscopy. The overall reporting threshold for most of the targeted elements was 0.05 µg/mL, which corresponds to 0.5 µg/g for the most commonly utilized extraction stoichiometry (1 g of material per 10 mL of extracting solvent). The targeted elements could be classified into four major groups depending on the frequency with which they were present in the over 250 extractions reported in this study. Thirteen elements (Ag, As, Be, Cd, Co, Ge, Li, Mo, Ni, Sn, Ti, V, and Zr) were not extracted in reportable quantities from any of the test articles under any of the extraction conditions. Eight additional elements (Bi, Cr, Cu, Mn, Pb, Sb, Se, and Sr) were rarely extracted from the test articles at reportable levels, and three other elements (Ba, Fe, and P) were infrequently extracted from the test articles at reportable levels. The remaining eight elements (Al, B, Ca, Mg, Na, S, Si, and Zn) were more frequently present in the extracts in reportable quantities. These general trends in accumulation behavior were compared to compiled lists of elements of concern as impurities in pharmaceutical products. LAY ABSTRACT: Nearly 100 individual test articles, representative of materials used in pharmaceutical applications such as packaging and devices, were extracted under exaggerated conditions, and the levels of thirty-two metals and trace elements (Ag, Al, As, B, Ba, Be, Bi, Ca, Cd, Co, Cr, Cu, Fe, Ge, Li, Mg, Mn, Mo, Na, Ni, P, Pb, S, Sb, Se, Si, Sn, Sr, Ti, V, Zn, and Zr) were measured in the extracts. The targeted elements could be classified into four major groups depending on the frequency with which they were present in the extractions reported in this study: those elements that were not extracted in reportable quantities from any of the test articles under any of the extraction conditions, those elements that were rarely extracted from the test articles at reportable levels, those elements that were infrequently extracted from the test articles at reportable levels, and those elements that were more frequently present in the extracts in reportable quantities.

Evaluation of the General Solution Compatibility of Polymer Materials Used in Medical Devices such as Syringes.

The general compatibility between various polymers (plastic and elastomeric materials) commonly used in medical devices (e.g., syringes) and common solution-based pharmaceutical products was examined. Processes affecting material/solution compatibility that were considered included drug binding and material leaching. Considering binding, material/water equilibrium binding constants (E(b)) were determined for 14 organic solutes and the test materials. Correlations between the measured binding constants and the organic solute's octanol/water and hexane/water partition coefficients were obtained. In general, the elastomeric materials behaved similarly and interacted with acidic compounds differently than with neutral compounds. Alternatively, the plastic materials typically used in device components such as syringe barrels were relatively inert in the sense that they only minimally bound even the most lipophilc compounds. Considering leaching, both organic entities and trace elements/metals were extracted from the elastomers over the extraction pH range investigated. The plastic materials generally had lesser quantities of organic leachables than did the elastomers and contained little, if any, extractable trace elements/metals. LAY ABSTRACT: Polymeric materials are commonly used in medical devices such as syringes. The plastic materials may interact with drug products contained within the device, potentially affecting the quality of the drug products. These interactions may include leaching, which is the migration of entities out of the material and into the drug product, and binding, which is the migration of substances out of the drug product and into the material. This paper examines the magnitude of leaching and binding for several materials that can be used in syringe parts such as the syringe barrel, plunger, and tip cap.

Impact of Formulation and Processing Parameters on Silicone Extraction from Cyclic Olefin Copolymer (COC) Syringes.

The effect of various formulation and process parameters on the extraction of silicone from siliconized cyclic olefin copolymer (COC) syringes is reported. The impact of proprietary silicone curing process on COC syringe barrels was evaluated with respect to the rate and extent of silicone extraction. Similarly, the impact of formulation parameters such as pH, ionic species, and cosolvents on silicone extraction was also evaluated. The rate and extent of silicone extraction into contact solutions was inversely related to the degree of completion of the silicone curing process. The rate and extent of silicone extraction in solution were highest upon exposure to extreme pH solutions. The silicone extraction data indicate that the silicone curing process and formulation parameters have a profound effect on the rate and extent of silicone extraction into solutions. LAY ABSTRACT: Silicone oils are used in medical syringes to provide lubrication. Prefilled medical syringes contain solutions into which silicone oil components may migrate. This study examined the degree to which silicone components migrated into different solution matrices. The impact of different levels of proprietary silicone curing processes on the migration of silicone components in contact solutions was also examined. This study also examined the impact of various formulation parameters (pHionic strength and cosolvents) on the degree to which silicone components migrated into solutions. Solution pH had the greatest effect on silicone migration with higher levels of silicone measured in solutions at the pH extremes. Curing of the silicone (reaction of the silicone with the syringe materials) also had significant impact. High curing levels resulted in less silicone migrating into solution as compared to levels seen with syringes with low curing levels. Thus it was demonstrated that both the nature of the solution stored in the syringe and the degree of silicone curing on the syringe barrel had substantial impact on the amount of silicone that migrated from the syringe components into the solution contained within the syringe.

Strategy for assessing the leachables impact of a material change made in a container/closure system.

Container/closure systems are extensively characterized in terms of their propensity to contribute leachable substances to the drug products they contain. Such a characterization is relevant until a change occurs in the composition or production of the container/closure system itself or the raw materials it is comprised of. When such a change occurs, it is necessary to ascertain the impact that the change would have on the validity and applicability of the previously performed leachables assessment. A general methodology for performing change control evaluations is developed in this manuscript and is illustrated via the use of a case study.