An FDA review of data indicated that, since 2003, the majority of injectable-product recalls related to particulate contamination have involved glass, metal, and the formation of crystals, according to an agency spokesperson. These recalls have contributed to the pharmaceutical industry’s heightened awareness of glass delamination (i.e., the formation of glass flakes in a vial), which could affect drug quality and patient safety. To confront this growing problem effectively, drugmakers must understand its causes.
Glass delamination results from the interaction between the product formulation and the glass container. Formulations with a high pH, and those that include phosphate and citrate buffers increase the risk of glass delamination, according to John Shabushnig, senior manager at Pfizer, leader of the Parenteral Drug Association’s (PDA’s) Visual Inspection Interest Group, and member of the US Pharmacopeia’s Visual Inspection Expert Panel.
Changing a product’s formulation to prevent glass delamination is not a straightforward proposition, however. Many drugs, particularly biopharmaceuticals, require certain formulation components to remain stable. Although phosphate and citrate buffers can corrode glass, for example, the active molecule may require the attributes of those ingredients. “Any change to the formulation may affect the safety and efficacy of the product. Therefore, changes must be considered carefully out of concern for patient safety,” says Ronald Iacocca, senior research advisor for physical and structural characterization at Eli Lilly and Company.
Characteristics of the glass vial itself also can heighten the risk of delamination, and changing the vial that holds a formulation could be easier than changing the formulation itself. High alkali content in glass could accelerate erosion, so manufacturers should choose vials with low alkali content if possible, says Iacocca.
In addition, evidence suggests that high temperatures during the vial-forming process increase the risk of glass delamination, says Shabushnig. Appropriate control of temperatures during the glass-forming process is especially important when the containers will store corrosive product formulations. Drug manufacturers should ask vial vendors about their process control, and also test vials to ensure their suitability for the product in question.
Drugmakers could adapt their manufacturing processes in certain ways to reduce the risk of glass delamination. For example, treating the surface of the glass vials with materials, such as ammonium sulfate, can reduce the rate of glass erosion, says Shabushnig. Terminal sterilization also is a risk factor that, together with specific products, could cause delamination. But drugmakers would consider alternative sterilization methods only in rare cases.
Storage conditions also should be evaluated. High product-storage temperatures and long exposure times can increase the rate and severity of glass delamination. Firms should examine both factors during stability testing to determine the appropriate expiration date for a given formulation.
Plastic primary container–closure systems are an option, but they may interact with the drug product like glass does, thus creating an undesirable extractables and leachables profile. In addition, polymers may not afford the necessary protection against oxygen or moisture that glass does.
It typically takes months or years for glass delamination to occur, so the phenomenon cannot be detected as part of routine 100% inspection during manufacturing. Ideally, drugmakers should identify and address this form of particulate contamination during product development, says Shabushnig.
“The phenomenon is best investigated as a systems-based approach by looking at the interaction between the drug product and the glass together,” says Iacocca. Drug-specific compatibility tests are the most important way of mitigating delamination in marketed products, he adds. These tests could be the first step toward deciding how to prevent this potential source of particulate contamination.
For more information about glass delamination, see Ron Iacocca’s article in the November “Analytical Technology” supplement to Pharmaceutical Technology.