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Byline author: Daniel Kramer, Senior Development Scientist
Co-author: Rob Schaut, Senior Research Scientist

For years, the pharmaceutical industry has been challenged by the risk of delaminated flakes in sterile injectables and associated product recalls 1. Corning developed Valor® Glass, a boron-free glass composition designed, specifically, for pharmaceutical use that eliminates delamination. The uniform surface chemistry and chemically-durable drug contact surface makes Valor Glass ideally-suited for sterile, injectable medicines.

A Boron-Free Glass to Eliminate Delamination

Glass can be a durable material well-suited for primary packaging. For decades, the industry has relied on borosilicate glass containers due to their hydrolytic resistance, but these glasses have not been used without their own issues 2. Delamination, the appearance of visible flakes / lamellae in filled vials has been the subject of many product recalls and regulatory advisories 3. Glass packaging suppliers attempt to mitigate the risk of delamination by changing manufacturing process steps, specifically during tubular conversion. These changes only reduce the risk of delamination, whereas Valor Glass eliminates it regardless of the tubular conversion process.

When vials are converted from glass tubing, the high-heat forming steps cause volatilization of glass components such as boron and sodium which can condense non-uniformly on the inner vial surface Figure 1. The boron-rich heterogeneities caused by this volatilization act as areas of reduced durability and are often concentrated in specific areas of the vial interior such as the heel. Figure 2 shows an example of a converted borosilicate container with enrichment of boron in the heel region of the vial. When the vial is exposed to corrosive solutions, these lower durability regions corrode faster than the underlying glass. This can result in the delamination of flakes into the solution Figure 3. Corning developed Valor Glass to eliminate the root cause of delamination—boron evaporation. The composition of Valor Glass maintains a glass network of elements used in Type I borosilicate containers e.g., silica, alumina with a boron-free formulation that eliminates delamination and improves overall extractables and leachables performance.

Consistent response at variable fill conditions

Valor® Glass vials have uniform surface chemistry, and therefore exhibit a consistent extractables response between low- and high-fill volume conditions. The durability of pharmaceutical packaging components is often evaluated through chemical testing such as hydrolytic testing and extractables and leachables. Differences in concentrations of extractables from glass containers can indicate altered surface chemistry, contamination, or consequences for drug stability. This testing provides quantitative metrics to monitor chemical durability, but some common test methods offer an incomplete description of the chemical response of glass packaging materials. Expanding on standard extractables testing 5. with additional fill volumes, solution chemistries, and accelerated aging conditions offers a more comprehensive screening of glass durability.

It is common to perform extractables testing of glass vials by filling the vials to 90% of their brimful capacity during accelerated aging. The resultant solution chemistry is then analyzed quantitatively e.g., acid titration, ICP-MS and these results are used to monitor glass corrosion. The extent of glass corrosion depends on many factors including solution chemistry, pH, time and temperature. Also, the corrosion response of formed glass containers is shown to depend on the ratio of glass surface area to volume of liquid SA/V used for extraction 4. Therefore, at lower fill volumes e.g. 12.5%, the concentrations of extractables will be greater than for the 90% fill condition.

These concentrations can be compared by normalizing for SA/V to compare the relative response of a glass vial at variable fill volume conditions as shown in Figure 4. For a vial with non-uniform surface chemistry, the concentration of extractables will be greater after normalization due to the regions of lower chemical durability. The extractables data in Figure 4a exemplifies this type of response where greater extractables are measured for a standard borosilicate vial even after normalization for SA/V. This response indicates non-uniform surface chemistry near the heel of the vial. Valor Glass vials exhibit less extractables overall, including lower concentrations of extracted aluminum (Al), than borosilicate containers as shown in Figure 4b.

Enhanced Acid/Base Durability and Hydrolytic Resistance

The uniform surface chemistry and enhanced chemical durability of Valor Glass vials demonstrate suitability for parenteral primary packaging applications. Hydrolytic resistance testing e.g. USP<660>, Ph.Eur. 3.2.1 is done using pure water 6., but additional insight on chemical durability can be gained from performing extractables testing across a wide range of pH acid/base conditions. The extractables for a glass container of a specific composition may change in identity and quantity as the pH of solution is varied. As shown in Figure 5, concentrations of extractables were greater for acidic and basic conditions than for water, and Valor Glass exhibited the least concentrations of extractables at all pHconditions relative to borosilicate containers.

Summary

The pharmaceutical industry has remained on the cutting-edge of innovation. However, the containers that store and protect the medicines haven’t evolved since the mid-19th century 2. Conventional borosilicate glass containers have inherent performance limitations, such as the presence of regions with poor chemical durability imparted by the converting process.

Valor Glass is engineered, specifically, to address several longstanding issues with glass quality that can lead to costly recalls. Not only does Valor Glass eliminate delamination, it also dramatically reduces glass particulates 7. and prevents cracks 8. that may otherwise lead to a loss of drug sterility. The boron-free composition of Valor Glass allows for uniform glass surface chemistry and enhanced chemical durability relative to traditional and delamination-resistant borosilicate glass containers. In addition, Valor Glass offers improved overall extractables and leachables performance and stronger hydrolytic resistance for parenteral packaging applications.

References

  1. D. Jaworkski, “Compliance Perspective on Glass and Injectable Drug Quality,” Parenteral Drug Association Glass Quality Conference, Washington DC, USA 2018.
  2. Robert A Schaut and W. Porter Weeks. “Historical review of glasses used for parenteral packaging.” PDA J Pharm Sci Technol pdajpst.2016.007377
  3. U.S. FDA, “Advisory to drug manufacturers: formatio of glass lamellae in certain injectable drugs.” 2011
  4. "Fill volume as an indicator of surface heterogeneity in glass vials for parenteral packaging", Kucko et. al, 2013
  5. USP Chapter <660> Glass Containers
  6. Ph. Eur. 3.2.1. Glass containers for pharmaceutical use
  7. Christopher Timmons, Chi Yuen Liu, and Stefan Merkle. “Particulate Generation Mechanisms during Bulk Filling and Mitigation via New Glass Vial.” PDA J Pharm Sci Technol pdajpst.2017.007724
  8. Robert A Schaut, Kyle C Hoff, Steven E DeMartino, William K Denson, and Ronald L Verkleeren. “Enhancing patient safety through the use of a pharmaceutical glass designed to prevent cracked containers.” PDA J Pharm Sci Technol pdajpst.2017.007807