2011 Advisory to Drug Manufacturers
In 2011, FDA issued an advisory to drug manufacturers regarding the potential formation of glass lamellae (glass fragments) in injectable drugs filled in small-volume glass vials. The advisory noted that the Agency was drawing attention to the issue because of several drug recalls in 2010 and 2011 due to the problem. The advisory also noted that there were no known adverse events reported or directly attributed to the problem; however, glass lamellae in injectable drug products pose potential risks, particularly when drugs are administered intravenously.
The advisory noted that a number of conditions have been associated with a higher incidence of formation of glass lamellae in drug products including, among other factors, glass vials manufactured by the tubing process at higher heat, drug solutions formulated at high pH, the duration of time the drug product is in contact with the glass container, and terminal sterilization processes. The advisory also provided recommendations to help prevent the formation of glass lamellae, along with literature references for the recommendations. These recommendations were also issued in a Question and Answer guidance for industry.1 Drug manufacturers can continue to follow these recommendations to reduce the likelihood of formation of glass lamellae.
Analysis of Safety Signals related to Glass Quality
The Agency evaluated surveillance data to determine whether there were any new or emerging safety signals related to quality issues associated with glass containers used in drug products on the market. FDA analyzed surveillance data from FY 2008 through FY2017. A new safety signal or change in frequency of reports of a known safety concern could reflect the emergence of an issue that would warrant a new or updated advisory by the Agency in order to inform manufacturers. However, FDA’s analysis of available data did not identify any new or increasing safety signals since the advisory was issued in 2011. At a recent glass quality conference with presentations by FDA and industry experts, participants noted progress has been made in improving glass quality for pharmaceutical packaging.2 Given this trend and the lack of any new safety signals related to glass quality issues, FDA will not update the 2011 advisory at this time.
FDA will continue to monitor drug quality, evaluate and assess incidents involving quality issues, and respond with appropriate actions when information suggests a need to correct an issue with drug safety or availability.
FDA Studies of New Container Closure Materials
In addition to evaluating surveillance data, FDA has also been engaging companies that have been working on developing new glass designs for use in pharmaceutical containers with a goal of addressing quality issues such as the formation of glass lamellae. Companies have approached FDA’s Emerging Technology Program (ETP)3 with requests to discuss their glass designs. The ETP promotes the adoption of innovative approaches to pharmaceutical product design and manufacturing through early engagement, and the ETP provides feedback on proposed technologies to facilitate anticipated regulatory submissions. Early engagement gives FDA reviewers a better understanding of a new technology when it comes in for review or is referenced in a submission. ETP’s role is to review a technology on its merits, not to endorse a company’s technology. Each technology still has to be evaluated in the context of the regulatory submission that it is associated with.
At the request of the ETP, the Office of Pharmaceutical Quality’s laboratory developed methodology and conducted studies to evaluate the performance characteristics of glass containers for injectable drug products. These laboratory studies will help inform future quality assessments and provide insight for feedback that can be provided to companies as they work on developing their products.
The laboratory evaluated the performance of a new aluminosilicate-type glass to assess if it is more resistant to delamination (i.e., lamellae formation), and two commonly used Type I borosilicate glass products. This work included evaluating the mechanical strength and the chemical durability of the glass vials. Chemical durability, including the likelihood of delamination, depends on a number of factors including the pH of the drug, processing and storage temperatures, and the amount of time the formulation is in contact with the container. FDA’s study of chemical durability approximated real world product conditions, including weeks to months of storage under a variety of pH and temperature.
For mechanical strength, compression testing was performed pre- and post-lyophilization and visual inspection was conducted for sample subjected to freeze-thaw testing. The chemical studies included analysis of stability samples by various techniques to assess the susceptibility of different glass vials to quality failures (glass delamination and leachables) under different conditions (e.g., pH, temperature, and storage time).
The studies demonstrated that the aluminosilicate glass vial type exhibited improved performance in terms of withstanding mechanical stress and scratching relative to the standard Type I borosilicate glass vials in the study. From the standpoint of chemical durability, under stress conditions (e.g., pH 10) the aluminosilicate glass vial type exhibited an improvement over one of the standard borosilicate glass vial, but there was no definitive difference in performance relative to the other borosilicate glass vial.
FDA will continue to evaluate our policies and related guidelines on drug containers to ensure manufacturers use containers that are appropriate for their specific operations, formulations, and labeled storage conditions. FDA remains committed to enabling the use of innovative products and approaches that support drug quality, and will continue to meet with companies through the ETP to support their development of novel manufacturing technologies.
2 https://www.pda.org/global-event-calendar/event-detail/2018-pda-glass-quality-conference, see also