The life sciences industry faces persistent challenges in assuring glass compatibility with products. One of the most serious challenges is that of glass delamination. Glass delamination, which occurs in vials, is a complex result of various factors including product composition, glass composition, glass forming temperature, and surface treatment. When delamination results in lamellae (flakes) or when other defects are present, patients are put at risk by compromised product quality. Using quality glass to begin with and understanding the potential for and prevention of glass issues are both excellent proactive measures in assuring glass quality. Choosing glass that is less prone to delamination, such as molded glass, reduces risk, as does implementing programs to proactively pretest packaging for stability. But when issues are encountered, strategizing fast and conclusive solutions is likewise important.
The best way to prevent defective glass products from entering the market is to conduct thorough and accurate quality investigations. Since defects can occur either during manufacturing or from adverse reaction to the contents, it is imperative to test the container both before and after product interaction.
There are multiple analytical techniques that can be performed when determining root cause of glass delamination in pharmaceutical containers. One technique of extraordinary value for imaging is Scanning Electron Microscopy (SEM). Understanding how electron microscopy can benefit glass delamination and defect investigations, and how it integrates with other analytical techniques for quality verification, will facilitate establishing a root cause.
There are two key imaging modes in SEM: Secondary and Backscattered Electron. The Secondary imaging mode delivers topographical information. So, when there are defects such as pitting and delamination in glass investigations, secondary mode will reveal these features. SEM in Backscatter mode is used to investigate elemental composition. When paired with elemental dispersive x-ray spectroscopy (EDS), SEM can provide definitive elemental information for compositional root cause detection.
3 Glass Delamination Case Studies
1. Delamination: Vial-Product Interaction
Visualization of the various stages of delamination can help to better mitigate risk
The discovery of small, shiny particulate in a parenteral product launched an investigation to identify the particulate and help determine its source. The glitter-like contaminant was very small – in the 1-2 micron range. The particulate, isolated using micro-vacuum filtration and then analyzed, was determined to be glass. Though glass had been suspected even before analysis, there was no known root cause. However, it was believed that the particulate had come from the production process and not the vial itself. Since the size and shape of the isolated particulate indicated delamination, the interior wall of the vial was investigated both above and below the fill line using SEM secondary imaging mode. The analysis uncovered pitting and flaking of the vial wall, a sure sign that the product was interacting with the glass causing delamination.
2. Quality Control: Surface Defects from the Manufacturing Process
Using the SEM to understand interactions between the glass surface and the product
During quality inspection of a final product vial, a vendor noted that the product remained on the vial wall noticeably longer than usual, causing abnormal wetting of the vial wall. Using the secondary imaging mode of the SEM (which can show slight surface abnormalities that are very difficult to visualize with other methods), the interior surface of the vial was investigated and abnormal surface features were discovered. Reference vials, ones that exhibited normal behavior, were also analyzed for comparison. The features in question were not found on the reference vials. Upon further investigation, it was discovered that the glass container vendor had recently made a slight change to the manufacturing process which was deemed at the time to be insignificant. However, this change was determined to be the root cause of the abnormal wetting.
3. Vial Contact Trauma: Filling Operations
Using the SEM in combination with other techniques facilitates root cause in vial trauma
Upon visual inspection, a glass vial was determined to have a fracture defect. Optical microscopy was the first technique used to investigate. The optical imagery indicated a contact point with high-level fracture complexity. Ripple marks and propagation lines further helped determine the impact point but the cause of the impact was still unknown. SEM/EDS, in backscatter mode, was used to directly analyze the fractured glass and a stainless steel residue was identified. Knowing a steel component had been involved in the fracture narrowed down the cause to two potential production points. Armed with this information, the instances of breakage could be further investigated to determine the root cause.
Scanning Electron Microscopy is a very powerful tool for delamination studies and other glass defect investigations. It provides topographical information not easily achieved using other methods. When coupled with the techniques described, SEM becomes even more powerful as an integrated part of a more sophisticated system that provides full component understanding. However, often delamination issues can be prevented by investigating accelerated delamination testing as specified in the soon-to-be-released USP<1660> Chapter (“Evaluation of the Inner Surface Durability of Glass Containers”) which recommends approaches to predict potential formation of glass particles and delamination. Visualization of the various stages of delamination can help better mitigate risk to the product, and the SEM provides an excellent means to collect this information.