Glass has long held a dominant presence in the pharmaceutical market for drug product container–closure systems. Desired properties for such systems include strength, transparency, stability, impermeability, and resistance to chemical attack. These characteristics are critical to preserving the quality of pharmaceutical products, and glass has long been the traditional material of choice. However, a recent rash of recalls concerning glass breakage, delamination, and related particulates has alerted the industry to risks associated with glass containers. As knowledge related to material suitability for use with drug products continues to expand, it is time to take a look at what is known (glass properties are well understood) and what is emerging (including the rising use of novel materials such as cyclic olefin polymers) to make an appropriate choice of material for container closure systems.

By law, drug containers are not to be reactive or additive so as to alter the safety or quality of a drug product. Recalls have shown that glass is not sufficiently inert to be in contact with today’s most sensitive pharmaceutical products. Mounting concerns related to glass include

• Breakage during filling or transport, resulting in rejects or breakage at the point of administration with potential to cause harm to patients
• Aggressive drug media formulation or components that can interact with glass resulting in issues such as protein aggregation
• Potential for drug product ion exchange (Li, Na, Mg, Ca, Al)
• A drug product pH shift due to dissolution
• Adsorption of certain products such as insulin, albumin, epinephrine, and atropine sulfate
• Formation of interactive products or precipitants such as MgSiO3 and BaSO4
• Shedding of glass lamellae (glass flakes).

In many cases, glass flakes have initiated drug product recalls. Also known as siliceous flakes, or lamella, these flakes result from glass delamination that can occur slowly over time in the presence of neutral, slightly acidic, or basic solutions. Lamellae are not easily observed and may occur during product storage and/or shipping. They can be observed in drug product solutions by swirling the liquid with light directed at 90 degrees to the direction of observation, but by then it is already too late.

In addition to chemical factors, manufacturing conditions may also predispose glass containers to delamination. Glass formulation and manufacturing processes can influence the potential for leachables and/or glass flakes. Delamination can occur at any point, including vial manufacture and heat treatment or sterilization processes.

Although no incidents have been associated with adverse effects, the presence of glass fragments poses considerable risk to patients. According to the US FDA, these flakes can cause embolic, thrombotic, and other vascular events when injected into humans. Lamellae also may cause development of foreign-body granulomas subcutaneously, as well as local injection-site reactions and increased immunogenicity.

Based on the rise in recalls due to glass delamination, the FDA has advised drug manufacturers to “re-examine their supplier quality management program with glass vials manufacturers to assure that this phenomenon in not occurring.” Selecting an appropriate container–closure system at an early stage of development will mitigate the risk of associated drug product recalls and contribute to supporting product stability, integrity, and delivery. Formulation characteristics such as pH, buffer type, and ionic strength in relation to the area of contact with the container can be considered early on. When the potential for glass issues is identified, an alternate material (e.g., a cyclic olefin polymer such as Daikyo Seiko, Ltd.’s Crystal Zenith brand) can offer a solution.

Look for more in an upcoming issue of BioProcess International.

Graham Reynolds is vice president of marketing and innovation in pharmaceutical delivery systems at West Pharmaceutical Services , Inc.; graham.reynolds@westpharma.com .