Glass Delamination in Aseptic Drug Products
Introduction
Since its inception, the pharmaceutical industry has used glass as a packaging material because it has many advantages over other materials. However, under certain conditions, the glass vials containing some biopharmaceutical products can shed thin, flexible fragments called “glass lamellae.” When these lamellae are shed from the interior surface of the glass vial directly into the product, it’s called glass delamination.
Most biopharmaceutical products are administered intravenously, so there is the risk of glass lamellae causing embolic, thrombotic, and other vascular events. In addition, they can act as protein nucleation sites, causing product aggregation and overall degradation of product quality.
News of FDA recalls became household news in 2010 when nine well-known drug products were recalled for being adulterated with glass flakes. These included Procrit and Epogen from Amgen and Hylenex from Baxter. Since then, there has been a steady stream of recalls each year. In 2014 alone, the FDA announced 17 additional commercial product recalls (1).
It takes a while for delamination to develop, making it difficult to catch. By the time it is seen, the product has probably already been used on patients. When a delamination event occurs, it is usually at a very low frequency. The three recalled Amgen batches all had glass delaminates in 0.04% or fewer of the total number of vials. Also, when found, lamellae are usually very small, making them even more challenging to observe. For Amgen, the lamellae were approximately one micron thick (2).
In addition to commercial products, many clinical-stage biopharmaceutical products have also had delamination issues causing clinical trial delays and the loss of millions of dollars worth of product. For companies with limited means, this could be the difference between a successful program and a company going out of business.
Causes?
Glass lamellae formation is linked to four conditions. The first is thermal stress during vial manufacturing. The most common vial for filling aseptic drug products is a tubular vial cut from long sections of glass tubes known as a cane. During this process, the glass is exposed to heat, which causes localized stress near the bottom of the vial during the cane cutting process and, in the vial shoulder, where extensive flaming is used to finish shaping the vial.
The second condition is thermal stress put on the vials when preparing them for drug product manufacturing, such as autoclaving and depyrogenation. The third source is through glass reactions with the product formulation buffer. Drug solutions formulated at high pH (alkaline) and with specific chelating agents such as citrate, phosphate, or tartrate are often associated with glass lamellae formation.
The fourth is a combination of product presentation, storage temperature, and length of time the drug product is directly exposed to the inner glass surface of the vial. Length of time has been shown to directly correlate to the potential for glass lamellae formation, and drugs stored at room temperature have a greater chance of glass lamellae formation than products stored at colder temperatures. Liquid formulations are also more susceptible to delamination than lyophilized or frozen presentations.
Decreasing Your Risk?
There are several ways to decrease the risk of a delamination event. The first is to choose a high-quality vial. In 2013 Schott introduced a vial specifically designed to minimize delamination risk. To produce this vial, Schott uses strict temperature controls to deliver a more homogeneous vial during the vial formation process.
Another option is molded glass vials, which are formed by injecting molten glass into a mold. When cooled, the mold is opened, and the vial is removed.?The heating and cooling can be homogenous and controlled, making these vials more resistant to glass delamination than tube-formed glass vials. Molded vials tend to be heavier and are generally intended for multi-use or long-term storage, whereas tube-formed vials are usually single-use.
A recently introduced alternative is molded plastic vials. If plastic is used instead of glass, it is essential to pick a vial construction compatible with the product formulation and does not leach into the product. It is also necessary to ensure measures are in place to control particles that can be shed from the plastic and that the product can be visually inspected in the vial after filling.
The second way is by carefully selecting the product's formulation and presentation. Some products are naturally more at risk due to their formulation. If an alkaline formulation must be used, the risk can be minimized by properly selecting glass composition (e.g., highly resistant, non-alkaline earth borosilicate glass). Also, as mentioned before, a liquid presentation is the most susceptible to delamination, while lyophilized and frozen presentations are less so.
A third way is to screen the chosen vial for the potential risk of delamination. Several quick test methods exist, all involving filling the test vials with either WFI or the products’ formulation buffer and then autoclaving them. After autoclaving, the vials are inspected for delamination by either checking for sodium extracted from the glass, staining with methylene blue, or looking for delamination microscopically.
The fourth way is to actively look for delamination during stability testing. Since delamination occurs at an extremely low frequency, they tend to be small, and only a tiny percentage of a tested batch is put on stability; this method may not necessarily catch delamination when it begins to occur. When checking, it is important to remember that delaminates tend to form near the bottom or shoulder of the vial; examining these areas should be emphasized in stability studies. If something that looks like delamination is seen, it should always be confirmed by a reputable vendor, such as McCrone Associates.
Finally, it is essential to keep an eye on the glass vendor through appropriate selection, qualification, and proper quality control of incoming vials.?Because of the number of product recalls, the FDA advises drug product manufacturers to periodically re-examine their glass supplier quality program to ensure that their vial?manufacturing and handling practices are robust enough to help prevent a glass delamination event from occurring.?
Conclusion?
When found, glass lamellae are usually very small and constitute a very low percentage of the total number of vials in an affected batch, making a delamination event challenging to detect. The delamination process also takes time to manifest itself. Because of this, by the time glass delamination is detected, the drug has probably already been distributed and given to patients.
Having to recall a product can have significant consequences for a company, including delaying a product's time to market, substantial financial loss due to scraped product, losing valuable market share in a competitive field, or preventing a commercial product's successful launch. For clinical-stage products, credibility may be lost with clinical site investigators affecting the ability to recruit patients for future clinical trials.?
Although the risk of a delamination event may be unavoidable, following the advice given in this paper can help decrease the risk of a delamination event.?If you have any questions, please get in touch with the author.
?References
2.?????Case Study – Glass Vial Delamination in a Biopharmaceutical Product, Rob Swift, Senior Principal Engineer Primary Container Engineering Rx. Amgen Corporation, 360 Glass Delamination Scientific Symposium, May 25, 2011, Arlington, VA.