Inside USP: US Pharmacopeia Proposes New Standard on Glass Quality

During the past two years, the growing problem of glass particles in injectable medications has led to a number of product recalls. The crux of the problem is the durability of glass containers. Specifically, the inner surfaces of some glass containers are less durable and thus more susceptible to delamination (i.e., the shedding of glass flakes from the vial's interior walls) than others. Numerous factors may affect glass durability. Although the impact of glass delamination on patient safety remains a point of debate, the presence of these particles is at the very least a serious quality problem that must be addressed.

In a March 2011 FDA advisory to drug manufacturers on the formation of "glass lamellae" in certain injectable drugs, the agency noted that, although no adverse events had been reported at that time, there is the potential for drugs administered intravenously that contain these fragments to cause embolic, thrombotic, and other vascular events; and when administered subcutaneously, to lead to development of foreign body granuloma, local injection site reactions, and increased immunogenicity. Several conditions have been associated with a higher incidence of lamellae formation, including glass vials manufactured by the tubing process (and thus produced under higher heat); drug solutions formulated with certain buffers; drugs formulated at high pH; and drug products that undergo terminal sterilization. Based on the sudden increase in this occurrence and subsequent recalls, the US Pharmacopeial Convention (USP) Packaging, Storage, and Distribution Expert Committee developed a new general chapter that recommends approaches to predict potential formation of glass particles and delamination. The new informational chapter, General Chapter <1660> Evaluation of the Inner Surface Durability of Glass Containers, will be proposed in the July–August 2012 Pharmacopeial Forum (PF) and was posted in advance of its publication on the USP website in May 2012.

For the purposes of pharmaceutical packaging, three types of glass are defined by USP General Chapter <660> Containers—Glass. Type I (borosilicate glass) is suitable for most products for injectable and noninjectable use. Type II is treated soda-lime glass, and Type III is soda-lime glass on the basis of the hydrolytic resistance of the glass. Glass, in the form of ampuls, bottles, cartridges, vials and prefillable syringes, is the container material of choice for injectable products, particularly biopharmaceuticals.

Recent recalls underscore the fact that not all Type I glass is equal in terms of quality. Glass delamination, which ultimately results in the appearance of lamellae, is a lagging indicator of structural instability of a container. Although delamination is the most obvious visual indicator of instability, it represents the final stage of a seriously weakened glass surface structure, and can be observed only at a point where prevention is no longer an option. As such, proper evaluation of the quality of glass containers is crucial.

Among the areas covered by USP's new informational chapter are:

• Good Glass Supply-Chain Practices: The chapter recommends steps for manufacturers in selecting a glass container vendor, including auditing the supplier, obtaining glass formulation from the supplier, designating formulation of Type 1 glass (33 glass or 51 glass), determining tubing glass source(s), and determining whether the containers have been treated with ammonium sulfate, among others.

• Glass Surface Chemistry: This section discusses use of the aqueous chemistry of surface glass to decide on the potential drug product formulation and treatment steps that could increase glass stability.

• Factors that Influence Inner Surface Durability: This section offers information on factors that have the potential to influence the durability of the inner surface of glass containers. These factors include glass composition, the conditions under which the containers were formed, subsequent handling and treatments, and the drug product in the container. The section notes that not all factors influence surface durability to the same extent, and their effects can be additive.

The draft general chapter also details screening methods to evaluate inner surface durability. These build upon General Chapter <660>. At present, each lot of Type I glass containers received by a pharmaceutical manufacturer must comply with the Surface Glass Test detailed in General Chapter <660>. Although this test provides an indication of the durability of the surface, it does not provide a direct correlation with the susceptibility to form glass particles or to delaminate. The most important variable that affects surface durability is the drug product itself (i.e., the interaction between the product and the container). The Surface Glass Test does not take the drug product into consideration. Therefore, as USP states in the general chapter, this test represents only the first step in quality control of surface durability, and additional screening methods should be employed.

Predictive screening methods help evaluate glass containers from different vendors, glass formulations, and post-formation treatments. The general chapter addresses the three key parameters that screening methods should employ as well as commonly used analytical methods for evaluating the three parameters. It notes that predictive tests should look for precursors that lead to delamination rather than flakes themselves, and should be able to quickly provide predicative indication of surface durability. The general chapter also details other testing that may be useful, particularly in evaluating interaction with specific drug products.

Formation of glass particles in injectable drug products represents a growing challenge. USP's new informational general chapter is intended to augment its current glass standards via recommended approaches for predicting the potential for this disintegration to occur. This may serve as a resource for manufacturers, and the organization is seeking input on its proposal. To read the full general chapter, and to learn how to provide comments, please visit www.usp.org/usp-nf/notices/evaluation-inner-surface-durability-glass-containers-posted-comment.

Anthony DeStefano, PhD, is senior vice-president of compendial science, and Desmond Hunt, PhD, is senior scientific liaison, both with the US Pharmacopeial Convention (USP).