OR WAIT null SECS
Agnes Shanley is senior editor of Pharmaceutical Technology.
Manufacturers and the US government are investing heavily in traditional and non-traditional forms and materials to ensure supplies of containers and delivery devices for COVID-19 treatments and vaccines.
The COVID-19 pandemic brought uncertainty into almost every aspect of life in 2020. As the pipeline of potential vaccines and treatments for COVID-19 grows, questions linger about which ones will succeed, how soon they can be brought to market, and whether the existing bio/pharmaceutical supply chain will be robust enough to support them.
Since May 2020, experts have raised concerns about the availability of primary parenteral packaging, particularly the vials, stoppers, and syringes that would be required to fill and package new prophylactics and therapies (1,2). Borosilicate glass, the workhorse container material, is generally considered the easiest and least expensive choice, but fundamental supply problems, including shortages of the types of sand required for medical-grade glass production, have raised concerns about future supply. Since 2015, industrial sand supplies have been dwindling, while illegal sand mining has led to an increase in crime in some nations (3,4).
Borosilicate glass vial manufacturers began to increase capacity in 2019 and are confident that supplies will be adequate to meet both existing market and pandemic requirements. On June 16, 2020, CEOs from three of the leading glass manufacturers and suppliers, SCHOTT Pharmaceutical Systems, Gerresheimer AG, and Stevanato Group, pledged to ensure sufficient supply of type-1 borosilicate glass vials and other containers for any COVID-19 vaccine and treatment, in any part of the world (5).
Despite the economic benefits of type-1 borosilicate glass, the material can present problems including breakage, lamination, and particulate formation, an issue that has led to expensive drug recalls in the past. With some drugs, the glass can interact with the formulation within the vial, triggering the need to reformulate, a process that can be extremely expensive, especially for oncology drugs and immunotherapies.
The past decade has brought improvements in glass making and vial design to address these issues. SCHOTT, for instance, offers hotforming technology designed to prevent vial delamination; coatings to improve processing and prevent glass and drug interaction; and an alternative vial geometry to minimize breakage, according to spokesman Björn Weller. On the services side, Stevanato Group and SCHOTT offer the option of shipping pre-sterilized vials to pharma customers, saving them the expense of sterilizing vials onsite.
However, new container forms and materials other than glass are also being developed to improve processing and transportation, and prevent potential immunogenic responses in patients. Valor, an aluminosilicate glass developed by Corning in partnership with Pfizer and Merck, is one such alternative. Its formula eliminates boron, which becomes unstable at the temperatures used to form glass. In traditional processing, boron can vaporize and be redeposited on glass surfaces, leading to variability in the chemical composition of the container. According to Corning, Valor reduces particulate contamination, improves durability, and can enable 50% improvements in filling and capping speed, compared with traditional borosilicate materials.
Glass-coated plastic vials are another alternative, and clinical trials are now underway for COVID-19 treatments using SiO2 Materials Science’s vials, which are made of cyclic olefin polymer with an ultrathin inner coating of silicon dioxide.
Another non-glass device has been developed by ApiJect Systems America, whose founder and CEO pioneered single-dose autodisposable injectors in the 1980s. ApiJect is collaborating with the RAPID (short for Rapid Aseptic Packaging of Injectable Drugs) Consortium, as part of its Jump Start program on the blow-fill-seal (BFS) formed, prefilled syringes. Composed of a container and a separate needle hub, the device’s parts would be shipped together and activated when combined at the treatment site. RAPID claims that, during a pandemic, the device could permit 330 million vaccine doses to be manufactured each week (6).
The US government and Big Pharma have been investing heavily in all these alternatives for fast-track COVID vaccine and therapeutic development and commercialization. In June 2020, the US Department of Defense’s (DoD’s) Biomedical Advanced Research and Development Agency (BARDA) awarded Corning a $204-million contract to supply Valor for COVID-19 therapies and vaccines and signed a $143–million supply deal with SiO2 Materials Science; the previous month, Pfizer entered into long-term Valor purchase and supply agreements with Corning, while the DoD and US Department of Health and Human Services signed a $138–million contract with ApiJect (7–10).
The choice of which container components and materials to use on injectable medicines, including vaccines, is anything but trivial, says Cindy Reiss-Clark, senior vice-president of commercial markets and commercial solutions at West Pharmaceutical Services, which specializes in elastomeric closures as well as seals, syringes and injection devices, and contract manufacturing services. The selection process requires meticulous testing and verification of compatibility, followed by formal stability testing and scenario planning for potential scale-up, should a therapeutic make it past clinical trials, she notes. “Failure to choose compatible containment and delivery components can result in impurities and/or reduced efficacy, with potentially devastating health impacts on patients,” Reiss-Clark says.
The time pressures posed by the COVID-19 pandemic have made the selection process even more challenging, but Big Pharma and small innovators are working with both traditional and alternative materials and exploring ways to improve the fill/finish process. Many are also considering new alternatives to parenteral delivery forms for the future.
Even before the COVID-19 pandemic, borosilicate glass vial manufacturers had made substantive investments in new supply and operational excellence programs to keep pace with a healthy biopharmaceutical market and ongoing 3-5% annual growth in demand. In 2019, demand stood at roughly 50 billion containers worldwide, according to Stefan Schmid, vice-president of global sales and marketing at SCHOTT, which has its own captive supply of raw material glass tubing. The company has poured approximately $1 billion into new glass tubing and conversion capacity at its facilities. By the end of 2021, SCHOTT expects to have brought on 40,000 tons of new glass tubing capacity, enough for 7 billion vials, says Fabian Stöcker, SCHOTT’s vice-president of strategy and innovation. During the pandemic, SCHOTT has optimized shifts and staffing to minimize impact on operations, working closely with customers and local authorities to prevent problems with plant access and other issues when border closings and travel restrictions were in force, he says .
Andrea Zambon, marketing and product management director for Stevanato Group, expects to see global glass primary packaging market consumption of between 45 and 50 billion units in 2020, reflecting approximately 5% injectables growth, with different levels of demand for vials, cartridges, and syringes. Peak demand for glass primary packaging linked to COVID-19 is likely to reach 1–2 billion, he says, but can only be confirmed once vaccines, treatments, and dosages are defined. “Another variable is the fact that some drug development projects will likely experience delays, due to the need to prioritize development of COVID-19 drugs,” he says.
Like other glass manufacturers, Stevanato Group, which also has an agreement to offer Corning’s Valor glass, has increased supply. “Since the outbreak of COVID-19, we’ve been securing supplies. We’ve hired more staff and redesigned shifts so that we can produce without any stop and deliver products while preserving our staff’s health and safety,” says Zambon.
Since the COVID-19 pandemic began, the biggest challenge for container manufacturers has been assessing true demand, given the huge number of therapies being explored. As Schmid puts it, 600 potential COVID-19 therapy and vaccine candidates are currently being developed around the world, but no one knows which-or how many-will be successful, or when. “Everyone is asking for vials, but we all know or must assume that only a few candidates will ultimately be commercialized. The multiplying effect of inquiries makes it difficult to assess true demand and timing,” he says. There are also questions about how demand will break down between single- and multi-shot (i.e., 2–mL vs. 10–mL) vials.
Established 10 years ago in Alabama, SiO2 Materials Science has begun to commercialize pharmaceutical applications, says Lawrence Ganti, president of customer pperations. Working with scientific advisors from Auburn and Harvard Universities, the Massachusetts Institute of Technology, the University of California at Santa Barbara, and the University of Chicago, the company hired Bob Pangborn, former head of research at Dow Chemical, as a chairman of the scientific board. SiO2 has refined a plasma-enhanced chemical vapor deposition (PEVCD) process that it uses to coat plastic (typically a cyclo-olefin polymer [COP] or cyclic olefin copolymer [COC]) with a 0.3–nanometer coating of pure silicon dioxide that is covalently bonded and cannot be removed. The process results in a material that releases no leachables or extractables, no metal ions, and no particles, says Ganti, thus preventing immunogenic side effects. Marrying SiO2 with plastics offers the oxygen barrier of glass which most vaccines and biologics require, in containers that won’t break, don’t need washing or depyrogenation, do not form leachables or extractables, and can be produced quickly. “We can build capacity that would take glass plants up to 24 months, in three months,” Ganti says.The vials also prevent immunogenic responses in patients. “Especially during pandemics, time is not on your side. You want to avoid reformulation at all costs,” he says. SiO2’s vials can be kept at temperatures as low as – 40 to – 70 °C, which are required for some drugs that use mRNA or DNA technologies.
Novartis began to work with SiO2 three years ago and uses its containers for Lucentis, its biologic ophthalmic treatment for infants, which was commercialized in December 2019. Currently, 13 other pharma companies are also working with SiO2, which is involved in 16 different clinical trials, a number of which are in Phase II and III. Three of the clinical trials are testing potential COVID-19 treatments, says Ganti.
The future may see increased use of alternatives to parenterals (i.e., transdermal forms such as microneedles [both solid and hollow-tipped types] and inhalable forms. A number of COVID-19 therapy development programs are examining these forms, which are also a specialty for Kindeva, a new drug delivery specialist that was formed when 3M spun off its drug delivery division earlier this year. Kindeva is building upon 3M’s legacy in inhalation and transdermal drug delivery, and CEO Aaron Mann sees tremendous potential for inhalable dosage forms, a major focus for the company’s R&D, formulation, development, and commercial business, in treating COVID-19. At the same time, he says, microneedle dosage forms are being explored in more COVID-19 vaccine research programs.
Fill-and-finish operations, so crucial to parenteral supply, are also being optimized. One approach developed by SmartSkin Technology (11) is currently being used by 14 Big Pharma companies to improve fill/finish lines. Developed 10 years ago by a biomedical engineering student at the University of New Brunswick, SmartSkin uses pressure sensitive, skin-like nanomaterials to make force-sensitive replicas of packaging containers. These replicas move via drone along with containers on the filling line, so that they experience and measure the forces acting on the containers, allowing conditions to be optimized and controlled. So far, SmartSkin has allowed users to reduce yield loss and defect-related downtime by more than 80%, reducing the workload on employees (e.g., for visual inspection and defect-related product investigations), and saving millions of dollars per year per filling line, says CEO Evan Justasson.
1. J. Bort, “Bill Gates Is Working to Fix a Surprising Problem Hindering a COVID-19 Vaccine: Finding Enough Glass Vials,” Businessinsider.com, May 11, 2020.
2. R. Bright, Office of Special Council, Complaint of Prohibited Personnel Practices and Other Prohibited Activity by the US Department of Health and Human Services, May 5, 2020.
3. M. Marschke, et al., “Roving Bandits and Looted Coastlines: How the Global Appetite for Sand is Fueling a Crisis,” theguardian.com, July 2, 2018.
4. M. Bendixen, et al., “Time is Running Out for Sand,” nature.com, July 2, 2019.
5. Gerresheimer AG, “Leading Pharma Packaging Companies Commit to Supply for COVID-19 Fight,” Press Release, June 16, 2020.
6. RAPID USA website.
7. Corning Incorporated, “U.S. Departments of Defense, Health & Human Services Select Corning Valor Glass Packaging to Accelerate Delivery of COVID-19 Vaccines,” Press Release, June 9, 2020.
8. Corning Incorporated, “Corning and Pfizer Announce Supply Agreement for Corning Valor Glass,” Press Release, May 28, 2020.
9. SiO2 Materials Science, “SiO2 Materials Science Receives $143 Million Contract from U.S. Government,” Press Release, June 8, 2020.
10. US Dept. of Defense, “DOD Awards $138 Million Contract, Enabling Prefilled Syringes for Future COVID-19 Vaccine,” Press Release, May 12, 2020.
11. A. Siew, “In-Line Force Analysis During Vial Filling,” PharmTechEurope 30 (1) 15 (2018). u
Vol. 33, No. 7
When referring to this article, please cite it as A. Shanley, "COVID-19: Shoring Up the Drug Delivery Infrastructure," BioPharm International, 33 (7) 2020.