A New Hybrid Material for Packaging COVID-19 Vaccines and Other Biologics: Combining the Best of Glass and Plastic

A Leader for COVID-19 Vaccines by Operation Warp Speed

The global hunt for a COVID-19 vaccine has been underway at breakneck speed by the best academic and industrial minds. This pursuit involves the development of both traditional and novel vaccine technologies aimed at undermining the SARS-CoV-2 virus. The Food and Drug Administration (FDA) has provided guidance for fast-tracking vaccine development and ultimately market approval of a safe and effective COVID-19 vaccine. At last count, four candidate vaccines are already in late stage clinical trials in the US and many more in the pipeline.

While pharmaceutical companies are highly focused on vaccine development, they are also considering primary packaging options to fill, store and distribute billions of vaccine doses worldwide. Selection is complicated by traditional borosilicate glass facing a global shortage due to unprecedented demand. This is further confounded by questionable sealing integrity of glass at cold storage temperatures and the omnipresent problem of breakage.^1-4 Ordinary plastics have naturally received a surge of attention but have their own drawbacks that can compromise drug efficacy and stability.^5,6

A new hybrid packaging solution has been developed that has companies such as Novartis as well as the US government taking notice by investing in the future of primary packaging. SiO2 Materials Science (SIO2) has developed primary packaging that combines the best of glass and plastic without their respective drawbacks. The introduction of SiO2 primary containers (i.e., vials and pre-filled syringes) for biologic drugs has strong support from the US government. Championed by the Operation Warp Speed Initiative, the US government awarded SiO2 a $143 million grant to accelerate production of vials and secure a domestic supply for the COVID-19 vaccine.

Drug Stability

Primary packaging plays a crucial role in the preservation and protection of the drug formulation from the time it is filled until the point of injection into a patient. Ideally, the packaging would be an impenetrable and inert barrier that blocks anything from migrating into the drug formulation. In addition, it would eliminate interactions that could pull the drug or its excipients out of the formulation. A package that will never break or leak and withstand extremes of physical, thermal and chemical abuse over its lifetime would also be ideal. Both borosilicate glass and ordinary plastic materials have their individual merits to satisfy some of the previously mentioned requirements but fall short of satisfying them all.^1-6 SiO2 has leveraged the principles of materials science and engineering to develop a hybrid primary container that blends the advantages of glass and plastic materials without their respective deficiencies. We believe that vials and pre-filled syringes constructed from this hybrid material are the closest thing to an ideal primary container on the market today.

The surface of SIO2 containers is composed of a material that is well suited for ensuring drug stability. The container itself is molded out of a medical grade, engineered cyclic olefin polymer. The polymer serves as the foundation for depositing a proprietary glass-like barrier coating system as shown in Figure 1. Each layer of the barrier coating system is deposited sequentially by a process known as plasma enhanced chemical vapor deposition (PECVD). This process, which originated from the microelectronics industry,^7,8 can deposit inorganic and organic nanomaterials with physical and surface characteristics that have been unachievable with conventional polymers. The molecular structure and layer architecture was specifically engineered to block migration of contaminants originating from the container or from the environment entering the drug formulation. Furthermore, the dense and inert glass-like chemical composition of the drug contact surface eliminates any metal ion leachables and resists hydrolytic attack, which is unachievable by any glass material.⁹ The entire barrier system is adhered to the polymer backbone through strong covalent chemical bonds that remain intact after extremes of chemical, thermal and mechanical stress.⁹

Extensive testing was conducted to demonstrate the performance integrity of the barrier coating system. SiO2 vials passed hydrolytic resistance and surface durability (i.e., delamination) tests according to USP <660> and USP <1660> guidelines, respectively. SiO2 developed its own internal set of rigorous tests that demonstrated hydrolytic and delamination resistance to formulations ranging in pH from 3 to 14 at elevated temperatures. SiO2’s testing was purposely designed to exceed the conditions of both USP <660> and USP <1660> to demonstrate the robustness of the barrier coating system.^10,11

Results of comprehensive extractables and leachables testing on SiO2 vials revealed that the drug contact surface was ultra-clean without any compounds originating from the underlying polymer. Any detectable compounds were at trace levels or well below the established analytical evaluation thresholds.^9,12

A full battery of compliance testing was completed on SIO2 containers to support drug product submissions. The compliance testing included compendial (i.e., EP, USP, JP), biocompatibility (i.e. ISO 10993) and toxicity (ICH-Q3D). This information is included in SiO2’s drug master file submission to the FDA.

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Lastly, the barrier to gases such as oxygen and ethylene oxide (i.e. for terminal sterilization) is taken for granted in glass since it is an impenetrable material to gases.^13,14 Most plastics, however, are breathable materials with measurable but varying permeation to gases that can compromise drug stability.^6,14 Drugs that are sensitive to oxidation can degrade more rapidly in ordinary plastic containers, which can significantly reduce shelf-life.^5,6 The pure silicon oxide layer has the highest density of any layer in the barrier coating system stack, which is an important requirement to block gas permeation. Its only about 20-60 nanometers in thickness and not in direct contact with the drug formulation due to the protective organosilica layer above.

Cryo and Cold Storage Container Closure Integrity

Ensuring that the seal between the rubber stopper and the vial is never broken (i.e. container closure integrity (CCI)) has as much to do about preventing leakage as does the loss of sterility. The vial dimensions, assembly, material properties and exposure to temperature extremes can make it difficult to measure, predict and control CCI. Some of the COVID-19 vaccine formulations in development (e.g. mRNA and DNA) require cold chain storage as low as -80 °C using dry ice.^15-17 Many cell and gene therapies demand cryogenic storage with liquid nitrogen in order to approach -196 °C.18,19 These storage requirements further complicate CCI for vial closure systems that were never designed for such extreme conditions.

SiO2 vials benefit from the tight dimensional control inherent in the cyclic olefin polymer molding process. The dimensions of cyclic olefin polymer vials can be controlled to extremely tight tolerances that are ten to one hundred times lower than what is capable of tubular or molded glass vials.²⁰ Improving dimensional precision helps to reduce and control stacking tolerances from the stopper and vial to ensure a good fit and seal from vial to vial.

Furthermore, the thermal coefficient of expansion of the cyclic olefin polymer is lower than elastomeric rubber stopper materials and is more closely matched compared to borosilicate glass. This means that the amount of shrinkage at cold or cryogenic temperatures will be more like the rubber stopper than glass and therefore reduce the risk of separation that could lead to CCI failure.

The coating itself does not interfere with sealing integrity nor dimensional variability. The total thickness of the barrier coating system is less than half a micron, which is at least two and a half times below the dimensional variability of the polymer vial. Additionally, the deposition of the coating is conformal to the internal surface of the cyclic olefin polymer vial. This means that the texture or roughness of the vial surface is completely unaltered after the coating is deposited. The rubber stopper therefore seals against the coating as it would against the cyclic olefin polymer.

The risk of the barrier coating system delaminating from the vial wall at cryogenic storage conditions was shown to be robust down to -196°C. SiO2 vials were completely immersed in liquid nitrogen for 6 hours and brought back to room temperature. The exposure to liquid nitrogen causes the polymer vial to shrink putting the barrier coating system under compressive stress at the surface. The oxygen transmission rate (OTR) measured before and after liquid nitrogen immersion was essentially the same as shown in Figure 2. This experimental evidence suggested that the barrier system was well-bonded and intact on the surface of the vial.

Cold storage CCI evaluations were conducted on 10 mL SiO2 vials. Vials were sealed with West Novapure stoppers at three different residual seal force settings and stored on a bed of dry ice at -80°C. The residual seal force is the amount of force exerted on the vial opening by the rubber stopper after the crimp cap is applied. CCI, determined by CO2 headspace partial pressure measurement, of SiO2 vials was low and unchanged after 3 months of storage compared to positive control vials with a 5-micron hole drilled through the wall by a laser (Figure 3). CCI cold storage testing will continue to be monitored out to at least 1 year. Separately, a cell therapy customer developing a viral vector vaccine already reported 1 year of drug stability in SiO2 2mL vials stored at -80°C filled with their proprietary formulation [unpublished communication].

Fill-Finish Compatibility

Compatibility with fill-finish manufacturing lines should be evaluated since the fill-finish equipment is designed with glass in mind. Therefore, the weight, surface finish, defect inspection, propensity for static charge and particle loads must be cross-examined to ensure smooth fill-finish operations with a new primary vial and syringe. SiO2 vials and syringes are designed to ISO standards. The ready-to-use packaging is based on established industry norms.

SiO2 has conducted extensive trials with the machine filling manufacturers to ensure compatibility. Although the weight of an SiO2 vial is approximately two-thirds of a similar sized glass vial, the center of mass was shifted down to reduce the risk of tipping over. The cyclic olefin polymer surface finish has not been observed to be an impediment to running smoothly on the fill-finish line. The inspection systems for defects on SiO2 vials requires some recalibration since what may be perceived as a serious defect in glass is only cosmetic in SiO2 vials.

SiO2 vials are manufactured in a cleanroom environment with automated controls and inspection systems that eliminate static charge, eliminate visible particles and reduce subvisible particles to well below USP 789 requirements (Figure 4). In-line deionizer systems ensure that vials nested in tub and tray configurations are free of static charge. This ensures that particles are not attracted to the vials during final secondary packaging prior to shipment for sterilization.

Secure Supply Chain and “Warp” Speed to Market

It might seem, at first glance, that vials with a glass-like coating would have the same supply chain concerns as standard borosilicate vials. However, SiO2 vials have no ties to the ordinary glass supply chain. The starting materials for the barrier coating system are organosiloxane liquids at room temperature and are more closely aligned with the supply chain for microelectronic devices and silicone polymers. The weight of glass-like material in each SiO2 vial is miniscule in comparison to the weight of cyclic olefin polymer. Only about 400 micrograms of glass-like coating is applied to a 6 mL SiO2 vial that weighs about 5.48g. In other words, 99.993% of an SiO2 vial is cyclic olefin polymer and the rest is the glass-like SiO2 barrier coating.

There is growing concern that glass manufacturers cannot meet the surge in demand for the launch of a COVID-19 vaccine.^21,22 This is compounded with the existing and growing demand of the biologics market. The ability to rapidly ramp up production capacity is essential to meet the short-term Operation Warp Speed goal of 300 million doses by January of 2021 and hundreds of million more after that. We believe that SiO2 technology has a clear advantage over traditional glass manufacturing in rapidly scaling up production capacity. This is enabled by state-of-the-art molding equipment for the cyclic olefin polymer vial and plasma coating modules that can add capacity as simple as plugging in additional USB devices to a laptop. Over 80 million vial units of annual vial capacity is already in place at SIO2 in Auburn, Alabama with another 50 million units expected to come on-line by December 1st. It takes approximately 3-4 months to add additional capacity.

Primary Container Selection for COVID-19 Vaccines

The current pandemic has the world preparing for the safe delivery of a COVID-19 vaccine. Uncertainty about the performance of ordinary glass under cold storage, the ability to scale up quickly, supply chain issues and fill-finish compatibility has vaccine developers and the US government considering better packaging options. We believe SiO2 is well-positioned to supply high quality products to regulated markets at very high volume. If compromise is not an option for new COVID-19 vaccines to manage risk, we believe SiO2 primary packaging provides the best possible solution.

References

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2. Chow, E. J.; Kitaguchi, B.; Trier, M., Effects of Subzero Temperature Exposure and Supercooling on Glass Vial Breakage: Risk Management and Other Applications in Cold Chain Distribution. PDA J Pharm Sci Technol. 2012, 66 (1), 55-62.
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7. Hamedani, Y.; Macha, P.; Bunning, T. J.; Naik, R. R.; Vasudev, M. C., Plasma-Enhanced Chemical Vapor Deposition: Where we are and the Outlook for the Future. Chemical Vapor Deposition - Recent Advances and Applications in Optical, Solar Cells and Solid State Devices, 2016, 247-280.
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10. USP <660> Containers—Glass
11. USP <1660> Evaluation of the Inner Surface Durability of Glass Containers
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13. Weikart, C.M.; Breeland, A. P.; Wills, M. S.; Baltazar-Lopez, M., Hybrid Blood Collection Tubes: Combining the Best Attributes of Glass and Plastic for Safety and Shelf-life, SLAS Technology, 2020, 25(5), 484-493.
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Author Biographies

Dr. Weikart has been with the company since its inception for 9 years and was responsible for leading the R&D efforts that resulted in the current parenteral product portfolio. Prior to joining the company he worked in Central Research at the Dow Chemical Company for 12 years in various R&D, engineering and leadership roles. Dr. Weikart earned a BS and PhD in chemical engineering from the University of Missouri-Columbia.

Dr. Langer is the David H. Koch Institute Professor at MIT, which is the highest honor that can be awarded a faculty member. Dr. Langer has received over 220 major awards and is the most cited engineer in history. He is one of 4 individuals to have received both the United States National Medal of Science (2006) and the United States National Medal of Technology and Innovation (2011). He served as a member of the United States Food and Drug Administration's SCIENCE Board, the FDA's highest advisory board, from 1995-2002 and as its Chairman from 1999-2002. He holds a BS in Chemical Engineering from Cornell University and a PhD in Chemical Engineering from MIT.