While many factors contribute to the recent surge in glass delamination recalls, it is important to remember that no recalls, clinical, or laboratory studies to date have shown any evidence of harm to the patient from "glass flakes or lamellae," and only a small fraction of drug products/container systems have a propensity for generating glass flakes. If one searches the literature, numerous examples of drug-product/glass-packaging interaction can be found in each of the past seven decades. The main reasons for increased glass delamination incidences are increasing inspection sensitivity for particles, high profile and costly recalls, and increased complexity of the formulations and, therefore, unknown criticality for corrosive attack of the containers. If glass delamination is observed, numerous types of alternate containers already exist in the market for packaging, and fast, reliable test methods are readily available for screening containers to evaluate the delamination risk for each drug-container combination.
Root causes for glass delamination
To understand and test for glass delamination, one must first understand the primary root causes: the chemical composition of the glass, the container manufacturing process, the chemical interaction of the drug product with the interior surface of the container, and the effects of processing. For parenteral drug products, Type 1 glass (United States Pharmacopeia [USP]<660>; ASTM E438) (1) is used, but the compositional differences between glasses is significant, varying by up to 10 weight percent for single elements. These compositional differences result in significant physical differences, primarily melting/working temperature, as glasses that contain more silicon (e.g., Type 1A glasses) require more heat to shape the container.
The majority of parenteral products use either molded or tubular glass containers. Molded containers require a single high-heat cycle (melting, pouring, blowing/pressing) and use compositions that are usually low in silicon and high in alkali/alkaline earth elements, resulting in interior container surfaces that are quite uniform in surface chemical homogeneity. Tubular containers made from glass cane require two high-heat cycles; the tubing is made first, then segmented or "converted" in a second heating process to the final container design. Careful control of the converting process in the base/heel and shoulder/neck regions is crucial to obtaining interior container surfaces that maintain the bulk-glass resistance to chemical attack, due to the evaporation of some glass components (i.e., alkali borates) in the worked regions of the containers. Glass-cane compositions are typically Type 1A or Type 1B, having higher amounts of silicon and lower amounts of alkali/alkaline earth elements than molded containers. While both moulded and tubular glass compositions used for parenteral packaging have high chemical durability, tubular compositions are generally regarded to have higher chemical resistance than molded compositions. Notwithstanding the two high-heat cycles, proper control of the converting process results in tubular containers with the equivalent non-delamination of molded containers, as demonstrated in the work of Ennis, et al. (2).
The chemistry of the chemical attack of glass by water-based liquids is driven primarily by leaching and dissolution. The primary attack mechanism at acidic pH is the diffusion of water into the glass and exchange of hydrogen (i.e., hydronium) ions with the alkali (i.e., sodium or potassium) ions, which is called leaching. The primary attack mechanism at basic pH is the dissolution of the silicate backbone (i.e., silicon-oxygen bonds) by hydroxide ions. The influence of the drug-product formulation, such as buffer type and ionic strength, also contribute to rate of chemical attack but are beyond the scope of this article. Processing steps performed after the vial is manufactured that influence the interior surface layer also affect the chemical durability of the container. The most aggressive processing step is the post-filling sterilization of the drug product by terminal steam treatment. A list of the most relevant factors influencing glass delamination is shown in Figure 1. Most pharmaceutical companies today have done a risk assessment using risk factors such as these and use them as a guideline for selecting and testing new drug-product and container combinations.
Figure 1: Mechanisms for glass attack and factors to assess for contributing to glass delamination. (ALL FIGURES COURTESY OF THE AUTHOR.)