Vaccine Administration: The Growing Role of Prefilled Syringes

Shelley,Suzanne;

Vaccines have been in the news and on the minds of people everywhere in recent years, thanks to the aggressive effort and timetable that was required to discover, develop, and disseminate the COVID-19 vaccines. Meanwhile, developers of other types of pediatric and adult vaccines have continued to advance the manufacturing, drug-administration, and packaging options that are used to support their products.

Vaccines are traditionally packaged and distributed in vials that contain either single or multiple doses. This approach requires the healthcare professional to prepare the vaccine for injection, withdrawing the precise dosage from the vial using a syringe, administering it into the patient, and safeguarding the remaining doses until the vial is empty.

Over the horizon for vaccines: Oral and inhaled dosing and transdermal patches

Prescribers and patients alike appreciate safe and easy vaccine administration. Today, of the 900 or so vaccine-development programs that are reported to be in development in Informa’s PharmaProjects database with known route of administration, one quarter are being evaluated in non-injectable formats, including oral, inhaled, and nasal routes, notes Cornell Stamoran, PhD, vice-president of corporate strategy and government affairs for Catalent, and about one third of these non-injectable programs are already in the clinical phases.

“There are also examples of promising R&D activities involving microneedle patches (which deliver the vaccine subcutaneously via a reservoir or coating on the needles), and, potentially, certain vaccines could be dried and stabilized in the microneedles to overcome issues related to logistics and ultracold storage conditions,” notes Vincenza Pironti, PhD, senior staff scientist, research and development, pharma services for Thermo Fisher Scientific. However, Pironti continues, “the regulatory landscape is still unclear about the acceptance criteria of these newer forms, as methods for release are still unclear, but these new modalities can represent potential solutions in the future.”

“Initial theoretical work and early R&D efforts suggest that the transdermal route may work, but more study and clinical trials are required to establish the safety and efficacy profiles and demonstrate benefits of this alternative approach, and then move toward the manufacturing considerations to allow these novel products to reach the market,” adds Stamoran.

In June 2022, Catalent announced it is carrying out a feasibility study with Israeli biopharmaceutical company MigVax, to investigate the possibility of delivering the COVID-19 vaccine to the oral mucosae (for absorption through the mouth and intestines) using Catalent’s proprietary Zydis Bio orally disintegrating tablet (ODT) technology, which creates a freeze-dried tablet that disperses in the mouth without water (1).

MigVax’s lead oral vaccine program for COVID-19, MigVax-101, which would be transported using the Zydis Bio ODT in unrefrigerated vehicles and stored in standard warehouses, “has shown positive results in preclinical tests,” said the companies at the time of the announcement. MigVax is also working with the Coalition for Epidemic Preparedness Innovations (CEPI) to develop oral tablet vaccines that are broadly protective against both SARS-CoV-2 variants and other coronaviruses, such as severe acute respiratory syndrome and Middle East respiratory syndrome.

Early work is also underway to pursue intranasal vaccines for COVID-19. Today, several dozen companies are at work, exploring not just aerosolized sprays but also nasally administered drops, powder, and gels (2).

References

Catalent, “Catalent and MigVax Sign Agreement to Develop an Orally Disintegrating Freeze-Dried Tablet Vaccine Against COVID-19,” Press Release, June 7, 2022.
J. Akst, The Scientist, June 13, 2022.

—Suzanne Shelley

A newer alternative—prefilled syringes (PFS)—has continued to gain favor among vaccine manufacturers and healthcare providers, thanks to several demonstrable advantages. During manufacturing, PFS are prefilled with a single dose representing one vaccination, in accordance with good manufacturing practices (GMPs).

“Today there is very strong preference among physicians and patients that if a therapy or vaccine can be supplied via PFS, it should, and the tangible results the PFS brings—where applicable—can create strategic marketing opportunities for drug makers,” says Cornell Stamoran, PhD, vice-president of corporate strategy and government affairs for Catalent. He is also a co-founder and co-chair of Catalent’s Applied Drug Delivery Institute, a research and advocacy arm founded in 2012 that explores how advanced drug delivery options can improve patient outcomes.

“Globally, PFS currently account for approximately half of the total market for prescription-based vaccine volume in the Americas and Europe, according to IQVIA’s MIDAS database,” notes Stamoran. (Note: The MIDAS database reflects vaccine doses that are dispensed with a prescription in retail or hospital settings, so the COVID-19 vaccines and other public-health-administered vaccines are not fully reflected in that data set.) Stamoran adds, “However, across the rest of the world, vial-based vaccines still make up the majority of the volume dispensed.”Thus, there is plenty of room for growth for this newer administration device.

The benefits of PFS for vaccines

The use of PFS has been shown to streamline and simplify vaccine administration, reduce dosing errors and wasted product, and minimize the potential for microbial cross-contamination and pathogen transmission, which can happen when multiple doses are withdrawn from a single vial. As a result, PFS are now widely used for annual flu shots, heparin injections, and a growing list of injectable therapies across multiple disease states.

“When vaccine is filled in a PFS, no further manipulation is required to safely administer it to the patient,” notes Vincenza Pironti, PhD, senior staff scientist, research and development, pharma services for Thermo Fisher Scientific. “For this reason, the risk of dose failure or injuries during manipulation is reduced to almost zero.”

Similarly, the use of PFS can help to streamline mass-vaccination efforts, especially in situations where the availability of trained staff may be limited. By not having to prepare traditional syringe-and-vial vaccines for injection at the point of care, frontline workers do not need the same level of training. This, along with the inherent sterility of vaccines in PFS form, is a key differentiating factor supporting broader use of PFS in developing nations and remote regions where the number of skilled medical professionals may be limited.

According to a 2021 article authored by Guillaume Lehée, R&D Innovation Leader for BD Medical—Pharmaceutical Systems, the use of PFS to vaccinate 300 million individuals in the United States in the event of a future pandemic could save more than three million hours of healthcare practitioners’ time (1).

Traditional vaccines (including the flu vaccines) that are based on proteins must be maintained at 2–8 °C (refrigerated conditions). “One potential downside to PFS is that in some retail or hospital pharmacies, vaccines stored in PFS take up more refrigerator shelf space (compared to traditional vials), so this may limit uptake by smaller pharmacies or smaller physician offices,” notes Stamoran of Catalent. “Similarly, if you’re trying to vaccinate in a developing country, having multi-dose vials may make more sense due to limited shipping capacity and refrigerator space; in more developed regions, those limitations may not exist.”

PFS provide advantages for vaccine manufacturers, as well. “There is no need to overfill the single-dose syringes,” Pironti says. “This increases the overall yield of the manufacturing process and preserves valuable vaccines and drug substances from losses.” By comparison, multidose vials are routinely overfilled and excess vaccine material is left behind when the multi-dose glass vials are discarded.

Meanwhile, “if the vaccine manufacturer is considering converting its product from a traditional vial-delivery system to a PFS, it may need to revise the formulation and carry out additional testing (and in some cases seek additional regulatory approval),” notes Stamoran, adding: “The developer will also need to explore other sources for packaging and materials, and all of this must be factored into the commercialization timeline and supply chain planning.”

Frozen and ultrafrozen vaccines—not candidates for PFS (yet)

Despite their advantages, PFS are not suitable for all vaccine types. Notably, the COVID-19 vaccines that are based on the messenger RNA (mRNA) technology platform (from Pfizer/BioNTech and Moderna) require frozen and ultrafrozen temperatures. They cannot, therefore at this time, be packaged and delivered in single-dose PFS form. “Generally speaking, today’s PFS are not yet proven to be compatible with ultrafrozen temperatures as the existing glass materials and other components may not stand up to the extremely low required temperatures,” explains Stamoran.

When PFS technology is able to advance sufficiently to support frozen and ultrafrozen vaccines, the breakthrough will be met with open arms, as the pursuit of more mRNA-based vaccines is already underway.

Every year, the seasonal results in roughly five million cases of severe illness and 290,000 to up to 650,000 deaths worldwide, according to the World Health Organization (2). And the currently available seasonal flu vaccines prevent just 40–60% of the disease in the best-matched seasons, according to the US Centers for Disease Control and Prevention (CDC) (3). In September 2021, Pfizer launched a Phase I study to evaluate a single-dose quadrivalent mRNA vaccine against influenza (4). Unlike conventional seasonal flu vaccines that are based on inactivated virus, the investigational process of designing vaccines based on mRNA “requires only the genetic sequences of the viruses, enabling more flexible, rapid manufacturing and the potential opportunities to improve upon the efficacy of current flu vaccines,” said the company at the time of the announcement. Hoping to capitalize on the “immense scientific opportunity of mRNA,” Beyond the seasonal flu vaccine, Pfizer is also exploring mRNA-based vaccines targeting other viral diseases, including HIV, Zika, and rabies, and is pursuing mRNA-based therapies in oncology and other genetic diseases.

Moderna is also pursuing flu vaccines based on mRNA, as well as mRNA-based vaccines against the mosquito-borne viral disease chikungunya, malaria, respiratory syncytial virus (RSV), endemic human coronavirus, Zika, Epstein-Barr virus, HIV, and others (5).Sanofi is also developing mRNA-based flu vaccines, while GSK is partnering with CureVac on both flu and second-generation COVID-19 mRNA vaccines.

Efforts to make PFS cold-compatible

With the advent of the ultrafrozen COVID-19 vaccines, “rubber materials and glass were challenged to demonstrate that the sterility barrier will be preserved even when ultra-frozen conditions are required,” says Pironti. “Potential mechanical solutions have been introduced and are in a preliminary phase, such as design alterations that allow the plunger to be rod blocked in order to avoid any unwanted movement, and customized combinations of plungers and syringes that could prevent vaccine degradation at extremely low temperatures.”

Stakeholders are also working to address this limitation by evaluating alternative materials, such as plastics or resins and glass-coated resin syringes that remain stable at extreme temperatures. “Ongoing studies and efforts to develop new materials are underway to address this challenge, with the hope of expanding the use of PFS for frozen and ultrafrozen vaccines in the next few years,” says Stamoran.

Becton, Dickinson and Co. (BD) completed a study in 2021 to assess the stability of drugs contained in glass PFS at frozen and deep-frozen temperatures (-20 °C to -40°C), and to evaluate how the syringes themselves cope at these extremely low temperatures (6). The company’s analysis involved syringes with different glass barrel coatings, different volumes, and other characteristics that could influence the response to deep cold storage. Tests were conducted on several combinations of glass barrel coatings, different formats (from 0.5 mL to 3 mL), different tip and flange designs, and multiple elastomeric closures with various state-of-the-art methods. “We’re encouraged by these results and look forward to partnering with pharmaceutical companies to further advance PFS in deep cold conditions,” said Bruno Baney, vice president of R&D for Pharmaceutical Systems at BD, at the time of the September 2021 announcement.

In December 2020, BD announced plans to invest roughly $1.2 billion over a four-year period to expand and upgrade manufacturing capacity and technology for PFS and other advanced drug-delivery systems across its six global manufacturing sites, and the company is adding a new manufacturing facility in Europe (to be online by late 2023) (7).

Meanwhile, in May 2022, BD and Mitsubishi Gas Chemical (MGC) signed a letter of intent to explore a partnership agreement to explore new ways to advance biologic drug development. The companies will investigate ongoing development of OXYCAPT—an innovation from MGC that “integrates the best of plastic and glass for plastic syringes”—to support the next generation of PFS for advanced biological pharmaceuticals. OXYCAPT is a multilayer structure applied on silicon-free plastic syringe barrels, to provide high breakage resistance, oxygen and vapor barrier, lower protein adsorption, very low extractables, high UV barrier, and pH stability, according to the company (8).

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When referring to this article, please cite it as S. Shelley, “Vaccine Administration: The Growing Role of Prefilled Syringes,” Pharmaceutical Technology 46 (8) 2022.