Particulate contaminants in parenteral drug formulations pose a significant risk for patients. During the past several years, the number of drug products contaminated with glass flakes generated as a result of glass delamination has increased, leading to recalls. Brought about through chemical attack of the glass surface, glass delamination can also lead to a decrease in the efficacy of the drug product and/or possible side effects due to leaching of some glass elements and the possibility of interaction with the drug product formulation, according to Dan Haines, scientific advisor, Pharma Services with Schott North America. The industry and regulatory bodies have thus taken a serious look at this problem.
Unfortunately, it is often the case that glass-delamination issues are only detected after the drug product is already on the market and stored in the container for several months. At that point, the course of action is to recall the product and find an alternative storage method. The best solution to this problem, therefore, is to avoid the potential for glass delamination all together. That, too, is challenging, however, because there is no single factor that causes glass delamination in a pharmaceutical setting, according to Haines. There is, therefore, no simple and easy method for screening potential containers.
Complex interplay of variables
Glass delamination is normally the result of chemical reactions between the drug and the interior surface of the glass container. “The occurrence of these reactions is the result of a complex interplay of different variables, such as the type of glass container, glass type (composition), pH range, drug type, and/or drug formulation (chemistry of the formulation). Importantly, a change in a single variable can make the difference between success and failure,” Haines observes.
In addition to the direct interactions between the drug formulation and the interior glass wall of the container, external variables can also play a role. Haines notes that a number of other risk factors have the potential to influence the possibility of delamination, including the storage time and temperature, the container-manufacturing conditions, and the sterilization process. He also stresses, however, that such risk factors alone are not predictive of glass delamination.
The chemistry of glass attack
The chemistry involved in the attack of glass by water-based liquids is mainly driven by ion exchange and dissolution. In acidic drug formulations, the primary attack mechanism is the diffusion of water into the glass and exchange of hydrogen ions with the alkali ions, which is called leaching. In basic drug formulations, the primary attack mechanism is the dissolution of the glass’ silicate backbone by hydroxide ions. Once ion exchange and/or selective dissolution occurs, a leached layer is formed that can detach easily from the interior surface of the glass container. The ion-exchange process can also create porosity in the glass. “In essence,” states Haines, “when a chemically complex drug product solution comes in contact with multi-component borosilicate glass, the two start interacting with one another.”
For drug products in phosphate-based buffer solutions, dissolution and reaction can also occur. “In this case, in addition to the dissolution of the elements of the glass into the drug solution, some of the elements (phosphates) from the drug product buffer solution interact with the glass. The result is a cross-layer reaction that can potentially cause a layer to come off of the surface of the glass,” Haines explains. What flakes off is actually a hybrid particle that results from the interaction of the drug product and the glass surface.
Although parenteral drugs must be stored in Type 1 glass (United States Pharmacopeia (USP) <660>, European Pharmacopoeia (EurPh) 3.2.1, and ASTM International (ASTM) E438) and meet requirements for hydrolytic resistance, not all glass compositions that fall under this category are the same (1–3). There is, in fact, significant variability in the elemental make-up of the glasses used for parenteral container manufacturing, and thus these different glass containers can interact quite differently with different drug formulations, according to Haines.
The container-formation method can also have an impact on the interactions between the glass and the drug product. Molded containers are formed in one step at high temperature and tend to have a high content of alkali/alkaline earth elements and a homogeneous surface chemistry. Tubular containers, on the other hand, undergo two heating steps, first to form the tube and then to form the bottom and neck regions. Control over the second step is critical for maintaining chemical resistance. The glass used for these containers tends to be higher in silicon. Generally, according to Haines, properly formed tubular containers are considered to be more chemically resistant than molded glass containers.
In addition, the glass used to produce parenteral drug containers is often treated in some manner. Ammonium sulfate sprayed into a container before annealing can reduce the alkalinity of the glass surface while a thin quartz (SiOx) coating can inhibit water diffusion.Testing early is essential
Regulations on glass delamination have not yet been published, but FDA has begun expecting pharmaceutical manufacturers to assess the risk for glass delamination and provide information on the proposed packaging for new drugs that may have a moderate to high risk for glass flake contamination. In addition, there is a USP guidance for the determination of the risk of glass delamination “Evaluation of the Inner Surface Durability of Glass Containers” (4).
Schott has developed a delamination-screening package aligned with the new USP guidance that involves testing containers drawn from real-time stability test samples or those generated under accelerated aging temperatures. The series of analyses are designed to determine the amount of chemical attack from drug products on containers and assess the risk of glass delamination occurrence through the shelf life of the drug product, according to Haines.
“The key to successful glass-delamination prediction is to test the drug product with the specific containers that are being considered for storage and distribution of the final formulation, and to do so as early in the drug development process as is feasible,” Haines adds. It is important, however, when using accelerated testing methods, to ensure that the method of acceleration does not change the glass, the drug formulation, or the method of glass attack, so the results will provide a true indication of the risk of delamination. He goes on to note that the use of multiple analytical techniques is necessary to obtain a comprehensive view of the behavior of the drug formulation in the container.
Schott employs a suite of six analyses. Visual inspection by eye and with the use of a magnifying video camera is used to determine if any particles or flakes are present. Optical inspection of the “critical” areas of emptied and rinsed containers using stereomicroscopy then enables the detection of glass attack, which appears as color banding due to changes in the chemistry of the glass surface.
In the areas where glass attack has been detected, the glass is scored and split to provide access to the interior surface of the vial, the morphology of which is investigated using scanning electron microscopy (SEM). Affected and unaffected areas appear differently in the SEM images as do areas where flakes have been generated. Inductively coupled plasma mass spectrometry (ICP–MS) of the drug formulation removed from the glass vial is then used to determine the concentration of dissolved “glass” elements, such as elevated levels of boron and sodium, which can indicate which mechanism of glass attack is operating.
Two additional tests are used only if further information is required. The particles obtained after filtration of the drug formulation can be analyzed using a combination of SEM and energy dispersive X-ray (EDX) spectroscopy, and the composition of the interior surface can be characterized by secondary ion mass spectrometry (SIMS) depth profiling.
Applying the analysis results
“The information obtained from these analyses can be used to help pharmaceutical manufacturers select the appropriate container for a given parenteral drug product. By learning about the mechanism of glass attack, it is possible to identify other glass compositions, glass container types (tubular versus molded), or coatings/treatments that will be appropriate for the formulation. The key is taking a proactive approach and determining the potential for glass delamination before a product goes to market, so that the most appropriate product packaging can be selected from the beginning,” concludes Gerry Wilkins, director of sales, US and Canada, Schott Pharmaceutical Systems.
- USP36–NF 31 General Chapter <660>, “Container–Glass” (US Pharmacopeial Convention, Rockville, MD), 2013
- EurPh 7.0, General Chapter 3.2.1, Glass Containers for Pharmaceutical Use (EDQM, Strasbourg, France, 2011), 303–308.
- ASTM International Standard E438, "Standard Specification for Glasses in Laboratory Apparatus" (2011)
- USP Proposed General Chapter <1660>, “Evaluation of the Inner Surface Durability of Glass Containers,” Pharmacopeial Forum 38 (4), in-process revision. 2012