Pharmaceutical glass, above all, should be inert to drug formulations and ensure the safe storage of medicines. While borosilicate Type I glass is the industry standard, shortages of some types of glass vials in recent years have been further exacerbated by the COVID-19 pandemic supply chain disruptions and need for high demand for glass containers for vaccines.
Manufacturers that implemented advanced supply-chain planning for fill/finish materials have weathered these challenging conditions so far, but difficulties are expected to continue for some time. Glass manufacturers are helping customers adjust to the situation with validation of alternative glass container solutions, including ready-to-use (RTU) molded glass products and strengthened aluminosilicate glass. Greater flexibility and collaboration across the supply chain have also surfaced as important factors for managing fill/finish material supply.
Drug products produced in glass vials and pre-filled syringes must be safe for the people who rely on the medicine they contain. That is the number-one priority for Curia (formerly AMRI), according to Jon Leisner, the company’s director of US procurement. “We take our responsibility seriously, to both our clients and the end-user, to provide sterile, quality, and compliant products,” he says.
For that reason, the most critical aspect of the glass used for pharmaceutical primary packaging needs to be as inert as possible so that it does not react with, add to, absorb, or allow external factors to change a drug product’s established safety, identity, strength, quality, or purity characteristics, explains Kevin McLean, quality and technical manager—Americas with SGD Pharma.
As such, notes Woocheol Chae, head of the drug product planning group at Samsung Biologics, the glass material must be chemically stable and not generate extractables or leachables (E&L), delaminate, or undergo other changes upon contact with the drug product. Minimizing E&L concentrations, adds Robert Schaut, scientific director of Corning Pharmaceutical Technologies, promotes the stability and purity of the drug product.
In addition, according to McLean, glass containers must protect their contents from the environment, and in some cases protect people from their contents, for example, from cytotoxic drug products.
In the United States, specific requirements for primary packaging as established by FDA are outlined in 21 Code of Federal Regulations Section 211.94. With respect to glass packaging, the global pharmacopoeias list three types of containers distinguished by their compositions and classified by their hydrolytic resistances—the extent to which 121 °C superheated water extracts alkali from the surface of the glass.
Type I borosilicate glass, for instance, has a long history of application and is the global standard for parenteral drugs due to its high hydrolytic resistance and ability to withstand extreme conditions, according to McLean. Type II and III are both soda-lime-silica glasses, but the former is treated on the inner surface to increase hydrolytic resistance.
Borosilicate glass primarily comprises silica and boric oxide and only contains small quantities of sodium. This composition, says Leisner, makes it resistant to heat and to enzymes. Its chemical inertness also makes it non-reactive with pharmaceutical products and reduces the risk of contamination, API degradation, and pH shifts.
All three types of glass must meet the container and closure system specifications of the United States Pharmacopeia and/or the European Pharmacopoeia, says Chae. The use of a colorant (mostly amber) is possible as a means for protecting the contents from exposure to light, he adds.
The COVID-19 vaccines placed additional performance requirements on the packaging system, according to Schaut. Key examples, he explains, include maintaining container-closure integrity below the elastomer’s transition temperature, maximizing filling-line throughput while minimizing particle contamination, ensuring mechanical robustness during freezing and transportation, delivering cosmetic quality to permit inspection of the contents, and serving as a functional barrier to contamination, gas, and light.
“The introduction of messenger RNA vaccines sets more specific needs beyond conventional glass vials, demanding either increased strength for optimal fill volumes in cold storage or a greater number of conventional glass vials with lower fill volumes,” Schaut continues. “These needs have created new challenges for fill/finish manufacturing and drug delivery that traditional pharmaceutical packaging is not able to address and is pushing the industry to move towards new, more advanced solutions to glass manufacturing,” he asserts.
Filling-line throughput has been particularly important for the COVID-19 vaccine due to the need to fill millions of vials as rapidly as possible. “There are many factors that limit the speed and efficiency of pharmaceutical filling machines, including dimensions and friction of the vial being processed,” notes Schaut.
Traditionally, Schaut observes, filling machines have been deliberately engineered with output constraints due to the physical interactions between the machine and conventional borosilicate glass vials. “Stress and friction generation on turn tables, tracks and trays, and particularly at junctions between intermittent and continuous motion can lead to glass breakage and human line interventions, which risks greater contamination of sterile environments,” he says.
Rapidly filling millions of vials with COVID-19 vaccines requires optimal filling efficiency and quality, which can be achieved in part using vials with a low coefficient-of-friction exterior surface, improved dimensional consistency, and strengthening to resist breakage, concludes Schaut.
The supply-chain for the production of tubular glass pharmaceutical-grade vials has been under stress for several years. Notably, the raw cane used to produce these vials was under strain due to changes in regulatory expectations in Asia, where there was demand movement from so-called low-borosilicate to mid- and high-borosilicate compositions, according to McLean.
The COVID-19 pandemic then placed an enormous global demand on the supply of tubular vials, creating concerns for global drug supply lines. “The supply/demand balance can be challenging to maintain when we are in a steady state, so the addition of a once-in-a-generation public health emergency has certainly put additional pressure on the marketplace,” says Leisner.
“The speed at which companies are required to move in order to address supply shortages is impacting every stage of the supply chain, from manufacturing to business processes to people,” Schaut adds.
Many of the large pharmaceutical companies, notes McLean, took a risk and placed orders for vials to package vaccines that were yet to be approved, locking in supply to meet the demand. “Ultimately, the supply-chain challenges for glass packaging materials observed over the last year are a result of a series of events, with a ripple effect across the industry,” he concludes.
An extended delivery period, which caused supply shortages, posed the biggest challenge over the last year, according to Chae. “Where it used to take 4–6 months to get a fill/finish material supply delivered is now extended to 12–20 months.” In particular, glass vials that are widely used for vaccines, such as 10R vials, were difficult to secure due to immediate increase in demand.
Despite such advanced planning by many, there has—and continues to be—a tremendous amount of pressure on the entire supply chain, according to Leisner. “Quite simply, demand has outstripped supply across the entire spectrum of fill/finish. It is not restricted to glassware. There have also been shortages of things [such as] plugs and stoppers, as well as all the consumables we need throughout the manufacturing process to fill and finish vials and pre-filled syringes, such as filters and filter bags,” he comments.
For companies that typically rely on tubular glass vials to package their therapeutics facing supply shortages, one option was to rapidly qualify other solutions, such as molded glass, as a backup or alternative. Molded glass can have some shortcomings compared to traditional glass, such as higher weight, non-uniform thickness, and reduced cosmetic quality, but does meet good manufacturing practice requirements.
“Forward-looking fill/finish operators continue to shore up their supply base and are thinking ahead. As vaccine administration is allowing the world to resume some degree of normal activity, COVID-19-driven demand remains high, and demand for other therapies that dropped during the pandemic is also rebounding. We are seeing more and more interest in molded glass as an alternative or back-up option to tubular glass given its global availability,” McLean observes.
It is not a simple solution, though. “The difficulty here is that the qualification and validation for alternate packaging can be extremely resource-intensive and can overwhelm smaller pharma companies,” says McLean.
Some have therefore turned to glass suppliers like SGD Pharma for regulatory support and to help with providing stability evidence and other needed data, according to McLean. “Many companies are seeking the expertise of their primary packaging partners to ensure approval and mitigate the risk of validations not being accepted. For instance, SGD Pharma is working with fill/finish organizations to provide support and information to help with the scientific justification of material changes,” he says.
There has also been growing interest in RTU glass vials in several pharmaceutical segments. RTU glass vials can be delivered pre-sterilized in optimized secondary packaging ready for fill and finish, skipping up-front washing and depyrogenation steps in an aseptic environment, allowing biotechs and drug manufacturers to speed up time-to-market, according to McLean.
“RTU technology has been around for a while, but only recently have we seen real interest, particularly in markets that require considerable flexibility in their operations, such as veterinary and biotech,” McLean says. For example, he points to the growing trend of personalized medicine as placing demand on innovative biotech companies for more flexible production capacity that can be supported by novel combinations of primary packaging.
To help meet that demand, SGD Pharma has introduced a number of RTU molded glass range extensions for fill/finish, including 50-mL vials in clear and amber glass in pre-sterilized tray secondary packaging and 20-mL vials in clear and amber glass in a nest-and-tub format.
“These new RTU primary and secondary packaging combinations developed in collaboration with Stevanato Group offer drug producers the flexibility they need to deliver innovative medicines to patients significantly faster because the drug master files (DMFs) are available,” McLean comments. “The nest-and-tub format, for instance, protects vials with no glass-to-glass contact and enables combi-line filling, the ideal option for smaller biotech companies looking for optimal flexibility,” he adds. In addition, biopharma manufacturers now have access to an integrated, flexible multiple filling line solution for different sources of primary packaging.