Lyophilization is widely recognized as an effective method for increasing the shelf life of labile drugs, including small molecule compounds and biotherapeutics. Of the top 100 drugs, ~16% are lyophilized and the percentage of lyophilized biotherapeutics is ~35%.1 These percentages are expected to rise with the increasing commercialization rate of biotherapeutics. The quality of a lyophilized drug relies on a complex inter-play of the product, the process, and the container. Glass containers remain the gold standard for lyophilization, although opportunities exist for improved performance.
The damage caused by vial-on-vial contact can generate significant amounts of visible and sub-visible glass particulates.2 The potential sequelae associated with the injection of glass particulates into a patient are widely known – e.g., phlebitis, pulmonary granulomas, systemic inflammatory response syndrome, and adult respiratory distress syndrome.3,4 The presence of particulate contamination can be monitored with various visual inspection methods. However, the opacity of dried cakes makes post-lyophilization detection of particles exceedingly difficult. The presence of particulate contamination also poses a subtler risk when combined with biotherapeutic products and their potential to induce the formation of anti-drug antibodies (ADA). Recent research has shown that ADA formation can be unintentionally increased by the presence of particulates. The mechanisms leading to this effect are thought to be similar to adjuvant materials that have traditionally been used to improve the immuno-potency of vaccines.5
Another limitation of conventional glass packaging is the possibility of breakage during the freeze-drying process. Strength-limiting flaws in the glass surface can be created by vial-on-vial contact and by contact between vials and components of a fill-finish line.2 These flaws can be activated by multiple sources of stresses during the freeze-drying process, including but not limited to:6
- Volumetric expansion of crystallizable excipients during freezing
- Adhesion and release of frozen product from sidewall
- Thermal expansion of the cake against the glass container during primary drying
- Excessive loading by the lowering of shelves within the lyophilizer to seat elastomeric stoppers
The implications of vial breakage depend on the specific product, the events surrounding a given production batch, and the standard operating procedures of the manufacturing site. At a minimum, broken vials decrease the product yield of the process. The extent of lost product may be isolated to just the broken container. In other cases, manufacturing sites may dispose of surrounding vials/trays due to particulate contamination concerns. An excessive amount of vial breakage can also trigger root cause investigations and exacerbate the process of cleaning the lyophilization chamber. Finally, in process breakage of vials containing high potency products can pose an additional safety hazard for manufacturing personnel.
Innovations in glass packaging have the potential to solve many of these historical problems. For example, Corning Valor® vials possess a low coefficient-of-friction (LCOF) exterior coating and an engineered stress profile via an ion exchange process that can enable superior performance in lyophilization. The LCOF coating has been shown to reduce glass particulate generation on filling lines by up to ~96%,2 thereby decreasing product contamination risks. The LCOF coating also inhibits the creation of strength-limiting flaws in the glass vial surface by mitigating the effects of frictive contact. The compressive surface stress inherent to Valor vials can improve container strength by up to 10x relative to conventional glass vials.7 The dual action of Valor® vials’ damage and breakage resistance results in a glass container that can better withstand the mechanical rigors of the lyophilization process.
The low temperature performance of Valor vials has been proven in multiple laboratory- and product-scale studies. For example, Valor vials showed zero to minimal breakage under aggressive freeze-thaw conditions relative to conventional glass vials (see Figure 1). In one large-scale line trial, approximately 120,000 Valor vials were processed on a commercial filling line and underwent lyophilization using a standard cycle. No Valor vials broke during the process and critical quality attributes of the product (cake appearance, residual moisture, etc.) were within standard process capability limits.
These results demonstrate that glass packaging need not simply be treated as a commodity product. Innovative products such as Corning Valor glass provides pharmaceutical manufacturers with a new solution to improve the quality of their lyophilized products.
- Price E. 2019. https://www.pcisynthesis.com/what-is-driving-the-growing-demand-for-lyophilization/, Accessed on March 30, 2020.
- Timmons CL et al. 2017. PDA J Pharm Sci Technol, 71: 379-392.
- Langille SE. 2013. PDA J Pharm Sci Technol, 67: 186-200.
- Bukofzer S et al. 2017. PDA J Pharm Sci Technol, 69: 123-139.
- Carpenter JF et al. 2009. J Pharm Sci, 98: 1201-1205.
- Machak DR and Smay GL. 2019. PDA J Pharm Sci Technol, 79: 30-38.
- https://www.corning.com/media/worldwide/global/documents/ValorProductInfoBrochure90319FINAL.pdf, Accessed on March 30, 2020.