The appearance of visible flakes or glass lamellae in various pharmaceutical products contained in vials has sparked a series
of product recalls over the past 18 months and initiated an industrywide conversation about the assessment of glass quality
for pharmaceutical applications. Recent FDA communications have recommended that all pharmaceutical companies renew conversations
with their suppliers on the topic of glass quality to ensure that patient safety and product quality are not compromised when
a glass vial, cartridge, or syringe is the primary packaging component (1).
Several recent studies in the pharmaceutical industry have examined the causes of and factors that influence glass delamination.
They recommended analytical tests that can assess the propensity of a pharmaceutical liquid to react with its primary glass
container (2–4). Glass delamination, however, is not a new phenomenon. In 1953, Dimbleby recognized the seriousness of glass
flakes in pharmaceutical products and prescribed a series of tests that could measure glass durability (5–8). According to
Dimbleby, visual inspection to monitor the presence of glass flakes should not be the sole test for assessing glass–product
compatibility.
A review of the glass-science literature reveals that the reaction of water and glass has been observed for nearly three centuries
and has long been recognized as a problem in the preservation of glass antiquities (9–11). When glass surfaces are exposed
to water, the network-forming oxides, such as silicone oxide (i.e., silica), leach from the surface, thus resulting in a glass
chemistry that exhibits less resistance to chemical attack. This glass layer, which has different mechanical properties than
the bulk substrate, will form flakes and spall (2, 3, 10). Corrosion mechanisms for glass are well identified (12–15). White
identified six specific mechanisms of corrosion (15). The mechanism that best describes glass delamination, or weathering,
is incongruent dissolution with the formation of noncrystalline layers. During this process, the gel layer of the glass that
exists in the presence of water dries out and forms a pattern of cracks.
Figure 1: Scanning electron micrographs that show evidence of glass–liquid interaction, including a) a vial interior that
has undergone delamination and shows signs of aggressive attack, and b) signs of modest glass-liquid interaction. No visible
flakes were ever observed in the liquid. (ALL FIGURES ARE COURTESY OF THE AUTHOR)
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Figure 1 shows images obtained from the interior of glass vials. Dimbleby and Iacocca identified some of the factors that
affect the durability of pharmaceutical glass, including the following:
- Terminal sterilization by autoclaving
- Thermal exposure during vial formation
- Glass chemistry
- Surface treatment, such as acid washing or ammonium-sulfate treatment
- The chemical nature of the liquid (3, 5, 7).
Currently, visual inspection has been the dominant technique to detect the presence of glass lamellae. The visualization of
flakes, however, is the last step in the delamination process. It is a lagging analytical indicator for a chemical incompatibility
between the exposed glass surface and its environment. As long ago as 1935, Dimbleby recognized that visual observations of
glass flakes were not sufficient. He recommended chemical analysis of the liquid in question for various factors, including
alkaline content, dissolved elements from the glass, and shifts in pH. With the development of electron microscopy, surface
analytical techniques, and quantitative analytical instrumentation, the titration techniques suggested by Dimbleby have been
augmented.
