Under certain conditions, glass vials can shed thin, flexible fragments called glass lamellae (Lachman, Lieberman, et al. 1986; Iacocca, Toltl, et al. 2010).

These lamellae are shed from the interior surface of the glass container directly into the drug and are difficult to detect by visual inspection. Several drugs have been recalled due to this problem: epoetin alfa, methotrexate, hyaluronidase recombinant, and fluorouracil (see Enforcement Reports on FDA’s Web Site).

No adverse events to date have been reported, nor can they be directly attributed to this phenomenon. However, there is the potential for drugs administered intravenously that contain these fragments to cause embolic, thrombotic, and other vascular events (e.g., phlebitis); and, when administered subcutaneously, to lead to the development of foreign body granuloma, local injection site reactions, and increased immunogenicity (Singh, Afonina, et al. 2010).

The following conditions have been associated with a higher incidence of the formation of glass lamellae: Glass vials manufactured by a tubing process (and thus manufactured under higher heat). These vials are less resistant than moulded glass vials and may shed lamellae more easily (Ennis, Pritchard, et al. 2001).

The processing conditions used to manufacture glass vials can be designed to mitigate the potential for later delamination. Drug solutions formulated at high pH (alkaline) and with certain buffers. Common buffers associated with lamellae formation include citrate and tartrate (Sacha, et al., 2010).

Length of time the drug product is exposed to the inner surface of the container. The time duration directly correlates to the potential for glass lamellae formation to occur during the product shelf life (Lachman, Lieberman, et al. 1986).

Drug products with room temperature storage requirements. Drugs stored at room temperature have a greater chance of glass lamellae formation than products stored at colder temperatures (Iacocca and Allgeier 2007). Terminal sterilization significantly affects glass stability (Iacocca, Toltl, et al., 2010). The referenced literature below includes recommended actions to help prevent the formation of glass lamellae. For example, for products “at risk,” the vial surface alkalinity can be minimized by proper selection of glass composition (e.g., highly resistant, non-alkaline earth borosilicate glass), appropriate selection and qualification of vendors, and proper quality control of the incoming vials.

Accordingly, FDA advises drug manufacturers of products to reexamine their supplier quality management program with the glass vial manufacturers to ensure that this phenomenon is not occurring. Further, the Agency reminds finished drug product manufacturers that CGMP regulations require that drug containers not be reactive or additive to alter the safety or quality of the drug. See 21 CFR 211.94; Rx-360’s Web site external Link Disclaimerdisclaimer icon, which has commented on the issue of delamination; and deviation reporting regulations for field alert reports (21 CFR 314.81) and biological product deviation reports (21 CFR 600.14).

References: Lachman, L, H Lieberman, and J Kanig, 1986, The Theory and Practice of Industrial Pharmacy, 3rd ed., Philadelphia: Lippincott Williams & Wilkins, 645–649, 796–798 Iacocca, RG, N Toltl, et al., 2010, Factors Affecting the Chemical Durability of Glass Used in the Pharmaceutical Industry, AAPS Pharm Sci Tech, DOI:10.1208/s12249-010-9506-9 Singh SK, N Afonina, et al., 2010, An Industry Perspective on the Monitoring of Subvisible Particles as a Quality Attribute for Protein Therapeutics, J Pharm Sci, 99(8):3302–3321 Ennis RD, R Pritchard, et al., 2001, Glass Vials for Small Volume Parenterals: Influence of Drug and Manufacturing Process on Glass Delamination, Pharm Dev and Tech, 6(3):393–405 Sacha, G., et al., 2010, Practical Fundamentals of Glass, Rubber, and Plastic Sterile Packaging Systems, Pharm Dev and Tech, 15(1):6–34 Iacocca, RG, and M Allgeier, 2007, Corrosive Attack of Glass by a Pharmaceutical Compound, J Mater Sci, 42:801–811 21 CFR 211.94: Drug product containers and closures 21 CFR 314.81: Other postmarketing reports 21 CFR 600.14: Reporting of biological product deviations by licensed manufacturers