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Characterization of Glass Delamination by TEM: Results from a New Sample Preparation Technique


Elaine F. Schumacher , Heidi M. Talesky, and Kristie J. Diebold McCrone Associates , Inc. , Westmont , IL 60559


analysis@mccrone.com


Abstract: A simple and effi cient fi ltration method is presented for isolation of thin particulate from liquid pharmaceutical products directly onto grids for analysis by transmission electron microscopy with energy dispersive x-ray spectrometry (TEM/EDS). The method is applied to the problem of glass delamination, wherein a liquid drug product reacts with glass packaging, contaminating the product with glass fl akes and residues. The fi ltration method facilitates preparation of representative samples for TEM/EDS, a technique shown to have advantages over scanning electron microscopy (SEM) with EDS for unambiguous characterization of thin particulate formed by glass delamination processes.


Introduction


Glass delamination is a serious and costly problem for pharmaceutical manufacturers and has led to several drug recalls in recent years. Delamination occurs when injectable solutions and suspensions react with glass packaging, resulting in contamination of drug products with glass fl akes and residues formed during glass dissolution. Reaction of glass with a drug may also lead to formation of secondary products. T e severity of glass delamination depends on several factors, including glass composition, presence of defects, glass container manufacturing methods, sterilization techniques, and drug storage conditions. Characteristics of the drug product such as pH or presence of buff ers will also infl uence the glass delamination process. A variety of analytical techniques may be used to verify that glass delamination has occurred, beginning with examination of the liquid drug product in the glass container, both visually and using a stereomicroscope. Particulate and fine residues are then typically isolated from liquid products by filtration and examined using light microscopy. T e fi ltered particulate may then be analyzed using scanning electron microscopy with energy dispersive X-ray spectrometry (SEM/EDS), a technique recommended for use in glass container screening studies as outlined in USP<1660>[ 1 , 2 ]. The interior surfaces of empty glass containers may also be characterized by wrapping them with tape and breaking them to expose inner surfaces while maintaining the spatial relationship of the fragments. T is is critical because specifi c areas such as the base or neck of a vial are more susceptible to delamination because of stresses incurred during the manufac- turing process. Interior surfaces may


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exhibit possible delamination precursors such as etching and pitting. If the process is more advanced, fl aking glass will be evident when surfaces are examined using light microscopy or SEM.


In some cases, visual examination, light microscopy, and SEM imaging may be suffi cient to observe the presence of glass delamination. However, elemental analysis is key to diff erentiating possible delamination products, including glass fl akes, coating fragments, dissolved glass residue, or secondary products formed by reaction between a drug component and a glass container. The most commonly used technique for obtaining compositional information about delamination materials is SEM/EDS, but there are some drawbacks to this approach. Removal of extremely thin samples such as delami- nation flakes or residues from filters for transfer to SEM substrates can be diffi cult. An alternative is to mount the entire filter on a substrate. Either preparation technique typically results in EDS spectra dominated by a signal from the substrate or the filter material, which is often polycarbonate (PC), and causes much smaller peaks for major elements present in the target thin sample ( Figure 1 ). Peaks for minor or trace elements may be entirely absent, thereby lessening the value of SEM/EDS for discrimination between glass and other materials that may be present.


Transmission electron microscopy (TEM) with EDS has been shown to off er advantages over SEM/EDS for analysis of very thin particulate resulting from delamination of glass vials


Figure 1 : SEM/EDS spectrum acquired at 5 kV from glass delamination fl ake on polycarbonate fi lter (left), and same spectrum with y -axis expanded to show peaks from glass components Si and O (right).


doi: 10.1017/S1551929516001127 www.microscopy-today.com • 2017 January


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