Tests for glass–liquid interaction
The tests described in this section do not detect glass lamellae in pharmaceutical liquids, but rather detect chemical incompatibilities
between glass and liquid months before glass flakes may be observed visually. These tests are leading indicators that delamination
Scanning electron microscopy of the vial interior provides the most direct evidence that the glass and the liquid it contains
are interacting. Figure 1a shows a scanning electron micrograph of a vial interior that has undergone a high degree of delamination,
and Figure 1b shows a micrograph of a vial that shows signs of glass–liquid interaction. Although some flakes can be seen
in the latter image, the extent of corrosion is far less, and no evidence of the extreme pitting seen in Figure 1a is present.
The utility of some of the tests proposed by Dimbleby and others must be considered in the context of the pharmaceutical product.
If the liquid is a solution containing a synthetic active pharmaceutical ingredient (API), the molecule itself can corrode
the glass (2, 3). In these instances, tests of pH and of the concentration of various elements (e.g., silicon), as measured
by inductively coupled plasma optical emission spectroscopy, can readily detect signs of glass incompatibility. Monitoring
silicon is particularly relevant because the leaching of silicon is the first step in the delamination process. Other elements
found in the glass may be detected in the parenteral solution, but they are not directly linked to the delamination. Figure
2 shows how pH and the concentration of silicon can change in a parenteral drug in which the API participates in the glass
The shifts in solution chemistry shown in Figure 2 do not present themselves so clearly in bioproduct formulations for several
reasons. First, the protein does not (and cannot) contribute to the glass–liquid interaction because it is too large to disrupt
the glass silicate network. Second, the pH of most bioproducts does not exceed 8.
Test methods for glass delamination
The interaction of a liquid with its glass packaging, however, is not the widely accepted definition of glass delamination.
The formation of glass flakes becomes a formal quality issue when the flakes are detected by visual inspection. To date, visual
inspection is the release test used to confirm product and glass quality.
Several challenges confront this approach. Glass delamination is a kinetic process that requires sufficient free energy and
time for the silica to leach and the flakes to form. Depending upon the product, this process can require weeks to months.
The time needed for release testing is not sufficient for delamination to occur. Material must be placed on stability to observe
delamination, and preferably stored under elevated temperature conditions (i.e., above the stated storage and use temperatures)
to stress the system.
Many questions have been raised about the ability of Hach HIAC light-obscuration instruments to detect nonvisible glass particles.
Limited research has been published on the issue. Ennis et al. used HIAC testing to monitor the formation of nonvisible particles
in vials in which delamination was occurring. All HIAC counts were within US Pharmacopeia limits, however (4).
A consideration of the principle of operation for light obscuration can yield insight into this question. Figure 3 illustrates
the operating principle behind light obscuration. Single particles are presented in front of a light source and are detected
either by their color or by their geometry. Certain shapes cause internal reflection and make the object appear dark. The
latter scenario is best illustrated by glass spheres. Soda lime glass (e.g., window glass), when in the form of a plate, does
not obscure light. As a sphere, however, it reflects light internally and appears to be dark. Thus, window glass can be detected.
For platelike or flakelike particles, light will be transmitted, not obscured. The only opportunity to detect a flakelike
particle is when the edges of the particle can be detected.
Figure 3: The measurement principle for light obscuration.
Laser-diffraction techniques have been used to monitor flake formation in delamination. The Spectrex laser particle counter
detects glass flakes in aqueous liquids (3). The only challenge with this instrument is that it may not provide an absolute
particle count. It does, however, clearly show trends in particle generation when delamination is active but cannot be detected
by visual inspection. Additional research is required to select the instruments that are best suited for sizing and counting