Setting a Clear Strategy for Primary Packaging

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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.

Safe and inert

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.

Pandemic-driven performance

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.

Pandemic-related supply-chain challenges

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.

Molded glass as an alternative

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.

Growing interest in ready-to-use vials

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.

Supply-chain needs

Catalent has not had any direct experience of significant supply shortages during the pandemic because the company honed in on addressing supply-chain needs, according to Melissa Buchanan, supply-chain director at the company’s Bloomington, Ind., site.

“To ensure minimal disruption, Catalent has tightly monitored its inventories, collaborated with supply-chain partners to protect critical supply needs, and committed additional resources to identify, navigate, and resolve potential supply-chain disruptions. This has included expanding safety stocks and extending the buying horizon to ensure sites have the necessary components to manufacture medicines, vaccines, and therapies for customers,” Buchanan remarks. Additionally, Catalent has developed improved business analytics to identify and track potential supply risks earlier, allowing more time to respond to challenges.

Similarly, Samsung Biologics benefited from resilient and flexible supply-chain-management operations, which ensured a stable supply by anticipating such disruptions and adopting proper contingency plans in advance, according to Chae.

The value of early supply-chain management

Even prior to the pandemic, it was important to have supply-chain strategies and contingency plans in place to support biopharma operations in the long-term and withstand market fluctuations and sudden material supply disruptions, Chae asserts.

With the COVID-19 pandemic, the industry has come to understand even more than ever before the value of early supply-chain management, according to McLean. “It may sound obvious, but successful drug manufacturers are those that manage their packaging supply with a proactive, rather than reactive, approach,” he states. Although there is an element of risk involved, he notes that securing supplies before product approval has huge benefits, particularly in situations such as the COVID-19 pandemic. The importance of having a backup packaging supplier has also been highlighted this year, McLean adds.

As a step to address the concerns over packaging supply uncovered during the pandemic, drug manufacturers are encouraged, says McLean, to start stability testing for alternative packaging materials before they experience shortages to mitigate risk and ensure business continuity in an uncertain climate.

Catalent, like many companies, found during the pandemic that the use of online and virtual tools, including improved data analysis for business-decision making, was vital to success. “These types of tools are helping identify and track potential supply risks earlier, allowing more time and better options to react,” Buchanan remarks.

Leveraging flexibility and speed

For Leisner, the pandemic has underscored the need for greater flexibility. “The pandemic has shown that the drug-development and manufacturing industry needs to build more diversity and agility into its processes and place an emphasis on phase-appropriate quality practices,” he asserts. “COVID-19 may not be the last pandemic that we’ll face in our lifetime, so we need to learn from the last 18 months and start making changes now,” he adds.

A specific example of how to increase agility in supply chains, Leisner highlights, would be to qualify multiple options for alternative components in the DMF. “That way we could diversify, if needed, and minimize disruption to manufacturing,” he says.

As a pharmaceutical glass packaging company, SGD Pharma has already learned to leverage flexibility, particularly the flexibility of the molded glass production process and run size, according to McLean. “During production, we form vials directly from the glass furnace, rather than converting from tubular cane that originates from a furnace elsewhere. We can therefore produce hundreds of thousands of containers per day on a single line and, when necessary, stop that line short and move to production of another size or design. In this way we can be flexible in production and add capacity quickly when needed,” he explains.

The pandemic, believes Schaut, has also highlighted the demand for increased efficiency and speed in pharmaceutical packaging and vaccine production. “New glass coating technology and high-speed filling lines can help enable pharmaceutical companies and contract manufacturing organizations (CMOs) to ramp-up capacity and throughput based on demand,” he asserts.

New levels of collaboration

A positive outcome of the COVID-19 pandemic has been increased collaboration across the biopharma supply chain. “The pandemic has required unprecedented cooperation between all partners involved, sharing information; working on various activities in parallel; and focus, dedication, and hard work by all the teams involved,” Buchanan states.

“We learned that collaboration is essential to meet demand and overcoming challenges quickly. Companies up and down the supply chain have been required to collaborate and find new solutions, be it material or technical, in order to meet the current need,” agrees Schaut. “Collaboration throughout the entire supply chain is essential to move quickly to implement solutions. From raw materials to fill/finish operations, companies are working together with an understanding that change is inevitable,” he says.

“Over the course of the last 18 months, Catalent has not only seen an increase in demand, but also an increase in collaboration and transparency across the industry, from innovators and other [contract development and manufacturing organizations] CDMOs, to suppliers and even regulators,” Buchanan continues. As a result of these new levels of collaboration, she notes that partners have been willing to make investments at-risk, allowing Catalent to bring more commercial capacity online, faster.

Along with greater willingness to consider other options, Leisner has observed a declining interest in single-source contracts, which he believes may become a thing of the past. “To get there, we will need to work in partnership across the ecosystem, and we all have a role to play,” he says. Fill/finish experts, for instance, need to help their customers understand the supply-and-demand risks of over-specification in regulatory documentation, while regulatory agencies could make re-opening DMFs easier by streamlining the current Resource- and time-intensive process.

McLean agrees that the inability of CMOs providing fill/finish services to make changes to primary packaging is an issue that should be addressed. “Primary packaging options for products validated on a contract manufacturer’s production lines are limited and therefore CMOs cannot respond quickly if changes are needed. Going forward, CMOs need to be included during validation of different container sizes and glass types,” he remarks.

Regulatory guidance as a navigational aid

Regulators are realizing, according to Schaut, that support for new materials such as aluminosilicate and strengthened vials, will help to curve supply shortages and meet increased capacity and safety needs.

FDA, for instance, is playing an important role in facilitating the industry’s ability to respond to the changing supply situation that has resulted directly and indirectly from the pandemic. “Through regulatory guidance issued in early 2021 (1), FDA is helping fill/finish operators navigate the qualification process for alternative glass vials and accelerate approvals,” McLean observes.

“The release of this guidance signaled FDA’s flexibility in permitting changes and substitutions between material types for primary packaging, as long as a strong risk-based analysis justifies the safety of doing so,” McLean explains.

Production for the pandemic’s duration

It is important to remember that the industry is not out of the COVID-19 period yet, says Leisner. “Vaccines are still in high demand and, while certain countries are realizing higher vaccination rates, we anticipate continued global demand. The need for booster shots also remains unknown. Consequently, tightness in the market remains, and supply will likely not catch up with demand for some time to come,” he comments.

Corning Pharmaceutical Technologies believes that the global shortage of borosilicate glass tubing used in the production of pharmaceutical glass primary packaging will continue to cause a bottleneck for fill/finish materials. “The need for COVID-19 vaccines is expected to continue on an annual basis in the form of annual boosters, new variant vaccines, and multivalent vaccines. Any tubing used for COVID-19 must be pulled from other drug products, potentially impacting the availability of non-COVID-19 related treatments,” says Schaut.

In addition, while COVID-19 vaccine manufacturers are currently filling at 10–20 doses per vial, Schaut notes that plans are already in place to shift towards single-dose vials and pre-filled syringes. Aging capacity in the industry also presents a long-term challenge for fill/finish material producers and the pharmaceutical companies who ultimately receive the converted packaging, he adds.

Overall, Schaut concludes that COVID-19 vaccine material demand is not expected to wane in the near future, which could lead to extended lead times until capacity throughout the supply chain is brought online.

Building capacity, a multi-year process

Capacity investment and new manufacturing technologies, such as high-volume manufacturing lines, are needed to help meet evolving industry needs, according to Schaut. Large vendors are making investments to increase capacity, which are expected to go into actual operation by mid to late 2022, says Chae. He expects that as demand for pharmaceuticals continues to increase, even if it is not related to COVID-19, the shortage of materials is likely to worsen in the short term.

Building in the additional capacity needed to meet the increased demand, both logistically and with regards to regulatory sign off, does not happen overnight; it is a multi-year process, adds Leisner. “As an industry, it will take time to create the additional capacity necessary to meet the COVID challenge while also protecting the supply of medicines to those who already depend on us,” he concludes.

Indeed, many announced borosilicate capacity investments are one to two years away, and most are slated for Asia and may not be available for the US market due to local demand, says Schaut. As the only American primary packaging pharmaceutical glass manufacturer, Corning is ready to assist by leveraging its North American manufacturing assets. “As previously announced, Corning and the US government have made significant investments in US manufacturing,” he says. The company is also expanding capacity around the world to support global supply chains, including a facility in Bengbu, China, which is slated to open ahead of schedule in in the third quarter of 2021.

Plastic potential

Glass, of course, is not the only material that can be used as containers for parenteral pharmaceutical products. Plastic is an alternative that is receiving increasing consideration in light of the shortages of glass materials. “With the enhancements in plastic molding technology, plastics may potentially become an alternative solution to glass in the long run,” Chae observes. Developments are also being achieved in blow-fill-seal technology, which he predicts may eventually replace vials and syringes to some degree.

Leisner adds that, while its excellent safety profile means borosilicate glass is a well-established industry standard, it does have limitations in some settings. As a result, he notes that a steady migration to polymer syringes, which are free of heavy metals and tungsten, has already been underway in recent years.

One key takeaway from Leisner is the fact that there never is a one-size-fits-all solution in the world of fill/finish. Plastic has its place, but it can be easily scratched and is not suitable for oxygen-sensitive drugs, he notes. It is essential to select the most suitable material for each drug product, considering the end user, route of administration, and manufacturing requirements.

Ongoing innovation

So what does the future hold for glass containers for parenteral drug products? McLean expects trends such as robust shipping to continue, with packaging innovators continuing their focus on glass vials that are resistant to breakages.

Innovators are creating new types of glass to overcome challenges associated with borosilicate, Leisner agrees. He notes that a relatively new-to-market glass has been designed to be break-resistant and to lower the risk of delamination by eliminating boron and sodium from the glass surface, which could increase the throughput on filling lines.

Chae points to aluminosilicate glass, which contains aluminum oxide and exhibits more tensile strength and resistance to high temperature and chemical corrosion. He also notes that new external surface-coating technology offers enhanced durability and productivity, while vials with built-in sensors facilitate process analysis.

“The introduction of strengthened aluminosilicate glass offers superior chemical durability, strength, and damage resistance as compared to traditional borosilicate vials. These qualities can help enable increased throughput and more reliable access to state-of-the-art medicines for patients, while maintaining a high level of quality assurance for pharmaceutical companies,” Schaut adds.

In addition, Schaut observes that advances in glass coating technology have enabled improved damage resistance, reduced particulate generation, and improved machinability leading to increased manufacturing capacity.

Going forward, Corning also believes that the industry will further adopt high-speed filling lines enabled by coated vial technology that can be used to help respond to rapid surges in demand for primary packaging, according to Schaut. “This technology is being adopted now, and we believe that it will become more and more prevalent as CMOs and pharmaceutical companies continue to expand capacity and upgrade existing lines,” he states.

Other trends outside of glass composition noted by McLean include growing interest in individual vial serialization with cradle-to-grave track and trace capabilities and the development of new RTU formats for larger capacity vials, which is of particular relevance to compounders, a once-again growing segment of the market.

“Compounding pharmacies have the ability to create drugs that were experiencing shortages, such as anesthetics, sedatives, muscle relaxants, and painkillers, and to combine multiple medications into a single solution to make them easier and cheaper to administer. Larger-size RTU vials will help compounding pharmacies manage sterility needs through the pandemic and beyond,” McLean states.

Reference

1. FDA, COVID-19 Container Closure System and Component Changes: Glass Vials and Stoppers, Guidance for Industry, (CDER, CBER March 2021).

About the author

Cynthia A. Challener, PhD, is a contributing editor to BioPharm International.