The Race to Develop the Pfizer-BioNTech COVID-19 Vaccine: From the Pharmaceutical Scientists' Perspective.

At the outset of the coronavirus disease 2019 (COVID-19) pandemic, it was clear that a vaccine would be crucial for global health efforts. The Pfizer and BioNTech teams came together in a race against the virus, working to design, test, manufacture, and distribute a safe and efficacious vaccine in record time for people around the world. Here, we provide backstory commentary from the pharmaceutical scientist perspective on the challenges and solutions encountered in the development of the Pfizer-BioNTech mRNA COVID-19 vaccine (BNT162b2; b2; Comirnaty®; tozinameran). We discuss the foundational science that led to the decision to use an mRNA-based approach. We also describe key challenges in the identification of an optimal vaccine candidate and testing in clinical trials, the continuous efforts to improve the vaccine formulation in response to changing global health priorities and facilitate vaccine accessibility, and how vast quantities of vaccine doses were manufactured and safely delivered to every corner of the globe, all without compromising quality, science, and safety. The key to successfully delivering a safe and efficacious vaccine within nine months was a result of extraordinary, real-time, parallel effort and across-the-board collaboration between stakeholders on a global scale.

Subcutaneous Delivery of High-Dose/Volume Biologics: Current Status and Prospect for Future Advancements.

Subcutaneous (SC) delivery of biologics has traditionally been limited to fluid volumes of 1-2 mL, with recent increases to volumes of about 3 mL. This injection volume limitation poses challenges for high-dose biologics, as these formulations may also require increased solution concentration in many cases, resulting in high viscosities which can affect the stability, manufacturability, and delivery/administration of therapeutic drugs. Currently, there are technologies that can help to overcome these challenges and facilitate the delivery of larger amounts of drug through the SC route. This can be achieved either by enabling biologic molecules to be formulated or delivered as high-concentration injectables (>100 mg/mL for antibodies) or through facilitating the delivery of larger volumes of fluid (>3 mL). The SC Drug Delivery and Development Consortium, which was established in 2018, aims to identify and address critical gaps and issues in the SC delivery of high-dose/volume products to help expand this delivery landscape. Identified as a high priority out of the Consortium's eight problem statements, it highlights the need to shift perceptions of the capabilities of technologies that enable the SC delivery of large-volume (>3 mL) and/or high-dose biologics. The Consortium emphasizes a patient-focused approach towards the adoption of SC delivery of large-volume/high-concentration dosing products to facilitate the continued expansion of the capabilities of novel SC technologies. To raise awareness of the critical issues and gaps in high-dose/volume SC drug development, this review article provides a generalized overview of currently available and emerging technologies and devices that could facilitate SC delivery of high-dose/volume drug formulations. In addition, it discusses the challenges, gaps, and future outlook in high-dose/volume SC delivery as well as potential solutions to exploit the full value of the SC route of administration.

Accelerating the development of novel technologies and tools for the subcutaneous delivery of biotherapeutics.

Subcutaneous (SC) delivery of biotherapeutics is well established as a route of administration across many therapeutic areas and has been shown to be effective and well-tolerated. It can offer several advantages over intravenous administration. This notwithstanding, there remain critical development issues and knowledge gaps in SC drug delivery. To articulate and address these issues, the SC Drug Delivery and Development Consortium was convened in 2018 as a pre-competitive collaboration of industry experts in drug delivery, device development, and commercialization. In this review, we outline the Consortium's vision and mission in advancing the development of patient-centered biotherapeutics and establishing a collaborative organization that facilitates open sharing of information and gives voice to diverse viewpoints from SC experts across industries and disciplines. Additionally, we describe the current landscape and challenges associated with SC administration of therapeutic proteins (specifically monoclonal antibodies) and offer insights into potential solutions to these challenges within the context of 8 problem statements developed by the Consortium to highlight key gaps, unmet needs, and actionable issues. Current and future opportunities to accelerate progress in the field through technological advances and the development of drug delivery tools are also discussed.

Long- and short-range electrostatic interactions affect the rheology of highly concentrated antibody solutions.

PURPOSE: To explain the differences in protein-protein interactions (PPI) of concentrated versus dilute formulations of a model antibody. METHODS: High frequency rheological measurements from pH 3.0 to 12.0 quantitated viscoelasticity and PPI at high concentrations. Dynamic light scattering (DLS) characterized PPI in dilute solutions. RESULTS: For concentrated solutions at low ionic strength, the storage modulus, a viscosity component and a measure of PPI, is highest at the isoelectric point (pH 9.0) and lowest at pH 5.4. This profile flattens at higher ionic strength but not completely, indicating PPI consist of long-range electrostatics and other short-range attractions. At low concentrations, PPI are near zero at pI but become repulsive as the pH is shifted. Higher salt concentrations completely flatten this profile to zero, indicating that these PPI are mainly electrostatic. CONCLUSIONS: This discrepancy occurs because long-range interactions are significant at low concentrations, whereas both long- and short-range interactions are significant at higher concentrations. Computer modeling was used to calculate antibody properties responsible for long- and short-range interactions, i.e. net charge and dipole moment. Charge-charge interactions are repulsive while dipole-dipole interactions are attractive. Their net effect correlated with the storage modulus profile. However, only charge-charge repulsions correlated with PPI determined by DLS.

Ultrasonic rheology of a monoclonal antibody (IgG2) solution: implications for physical stability of proteins in high concentration formulations.

The purpose of this work was to investigate if physical stability of a model monoclonal antibody (IgG(2)), as determined by extent of aggregation, was related to rheology of its solutions. Storage stability of the model protein was assessed at 25 degrees C and 37 degrees C for three months in solutions ranging from pH 4.0 to 9.0 and ionic strengths of 4 mM and 300 mM. The rheology of IgG(2) solutions has been characterized at 25 degrees C in our previous work and correlation of solution storage modulus (G') with protein-protein interactions established. The extent of aggregation was consistent with solution rheology as understood in terms of changes in G' with protein concentration. Thermodynamic stability of native IgG(2) conformation increased with increasing pH. The correlation between rheology and aggregation was also assessed at increased ionic strengths. The decrease in aggregation was consistent with change in solution rheology profile at pH 7.4 and 9.0. The results provide evidence of a relationship between solution rheology and extent of aggregation for the model protein studied. The implications of this relationship for formulation and physical stability assessment in high concentration protein solutions are discussed.

Transdermal delivery of interferon alpha-2B using microporation and iontophoresis in hairless rats.

PURPOSE: To demonstrate transdermal delivery of interferon alpha-2b (IFNalpha2b) in hairless rats through aqueous microchannels (micropores) created in the skin and enhanced by iontophoresis. MATERIALS AND METHODS: The Altea Therapeutics PassPort System was configured to form an array of micropores (2.0 cm(2); 72 micropores/cm(2)) on the rat abdomen. The transdermal patch (Iomed TransQ1-GS-hydrogel) was saturated with an IFNalpha2b solution (600 microg/ml) and applied for 4 h. Delivery was evaluated with and without cathodic iontophoresis (0.1 mA/cm(2)). Intravenous delivery (0.4 microg/100 g body weight) was performed to support pharmacokinetic calculations. RESULTS: IFNalpha2b was not delivered through intact skin by itself (passive delivery) or during iontophoresis. However, passive delivery through micropores was achieved in vivo in rats. A dose of 397 +/- 67 ng was delivered over 6 h, with steady state serum concentrations reaching a plateau at 1 h post-patch application. These levels dropped rapidly after patch removal, and returned to baseline within 2 h of patch removal. Iontophoresis-enhanced delivery through micropores resulted in a two-fold increase in the dose delivered (722 +/- 169 ng) in the hairless rat. CONCLUSIONS: In vivo delivery of IFNalpha2b was demonstrated through micropores created in the outer layer of the skin. Iontophoresis enhanced delivery through microporated skin in hairless rats.

Ultrasonic storage modulus as a novel parameter for analyzing protein-protein interactions in high protein concentration solutions: correlation with static and dynamic light scattering measurements.

The purpose of this work was to establish ultrasonic storage modulus (G') as a novel parameter for characterizing protein-protein interactions (PPI) in high concentration protein solutions. Using an indigenously developed ultrasonic shear rheometer, G' for 20-120 mg/ml solutions of a monoclonal antibody (IgG(2)), between pH 3.0 and 9.0 at 4 mM ionic strength, was measured at frequency of 10 MHz. Our understanding of ultrasonic rheology indicated decrease in repulsive and increase in attractive PPI with increasing solution pH. To confirm this behavior, dynamic (DLS) and static (SLS) light scattering measurements were conducted in dilute solutions. Due to technical limitations, light scattering measurements could not be conducted in concentrated solutions. Mutual-diffusion coefficient, measured by DLS, increased with IgG(2) concentration at pH 4.0 and this trend reversed as pH was increased to 9.0. Second virial coefficient, measured by SLS, decreased with increasing pH. These observations were consistent with the nature of PPI understood from G' measurements. Ultrasonic rheology, DLS, and SLS measurements were also conducted under conditions of increased ionic strength. The consistency between rheology and light scattering analysis under various solution conditions established the utility of ultrasonic G' measurements as a novel tool for analyzing PPI in high protein concentration systems.

Application of high-frequency rheology measurements for analyzing protein-protein interactions in high protein concentration solutions using a model monoclonal antibody (IgG2).

The purpose of this work was to explore the utilization of high-frequency rheology analysis for assessing protein-protein interactions in high protein concentration solutions. Rheology analysis of a model monoclonal immunoglobulin G2 solutions was conducted on indigenously developed ultrasonic shear rheometer at frequency of 10 MHz. Solutions at pH 9.0 behaved as most viscous and viscoelastic whereas those at pH 4.0 and 5.4 exhibited lower viscosity and viscoelasticity, respectively. Intrinsic viscosity, hydrophobicity, and conformational analysis could not account for the rheological behavior of IgG2 solutions. Zeta potential and light scattering measurements showed the significance of electroviscous and specific protein-protein interactions in governing rheology of IgG2 solutions. Specific protein-protein interactions resulted in formation of reversible higher order species of monomer. Solution storage modulus (G'), and not loss modulus or complex viscosity, was the more reliable parameter for predicting protein-protein interactions. Predictions about the nature of protein-protein interactions made on the basis of solution G' were found to be consistent with observed effect of pH and ionic strength on zeta potential and scattered intensity of IgG2 solutions. Results demonstrated the potential of high-frequency storage modulus measurements for understanding behavior of proteins in solutions and predicting the nature of protein-protein interactions.

Electrically enhanced transdermal delivery of a macromolecule.

The purpose of this study was to establish the delivery parameters for the enhanced transdermal delivery of dextran sulfate (MW 5000 Da). Full-thickness pig skin or epidermis separated from human cadaver skin was used. Silver-silver chloride electrodes were used to deliver the current (0.5 mA cm-2). For electroporation experiments, one or more pulses were given using an exponential decay pulse generator. The correct polarity for iontophoresis and pulsing was first established as cathode in the donor. The amount of drug delivered increased with increasing donor concentration up to a point, but not any further. The amount delivered also increased with pulse voltage, the delivery being twice as much as with iontophoresis alone (144.5+/-10.35 microg cm(-2)), when 6 pulses of 500 V were applied at time zero before iontophoresis (276+/-45.2 microg cm(-2)). It was observed that the amount delivered was a function of increasing pulse length when the apparent charge delivered was kept constant. Transport through pig skin (107.4+/-24.4 microg cm(-2)) was found to be comparable with that through human epidermis (84.9+/-18.4 microg cm(-2)). In conclusion, we have demonstrated the transdermal delivery of a 5000 Da molecular weight dextran sulfate using iontophoresis. It was also seen that iontophoretic delivery could be enhanced by simultaneous electroporation.