Vaccine process technology-A decade of progress.

In the past decade, new approaches to the discovery and development of vaccines have transformed the field. Advances during the COVID-19 pandemic allowed the production of billions of vaccine doses per year using novel platforms such as messenger RNA and viral vectors. Improvements in the analytical toolbox, equipment, and bioprocess technology have made it possible to achieve both unprecedented speed in vaccine development and scale of vaccine manufacturing. Macromolecular structure-function characterization technologies, combined with improved modeling and data analysis, enable quantitative evaluation of vaccine formulations at single-particle resolution and guided design of vaccine drug substances and drug products. These advances play a major role in precise assessment of critical quality attributes of vaccines delivered by newer platforms. Innovations in label-free and immunoassay technologies aid in the characterization of antigenic sites and the development of robust in vitro potency assays. These methods, along with molecular techniques such as next-generation sequencing, will accelerate characterization and release of vaccines delivered by all platforms. Process analytical technologies for real-time monitoring and optimization of process steps enable the implementation of quality-by-design principles and faster release of vaccine products. In the next decade, the field of vaccine discovery and development will continue to advance, bringing together new technologies, methods, and platforms to improve human health.

Accelerated Storage for Shelf-Life Prediction of Lyophiles: Temperature Dependence of Degradation of Amorphous Small Molecular Weight Drugs and Proteins.

Prediction of lyophilized product shelf-life using accelerated stability data requires understanding the temperature dependence of the degradation rate. Despite the abundance of published studies on stability of freeze-dried formulations and other amorphous materials, there are no definitive conclusions on the type of pattern one can expect for the temperature dependence of degradation. This lack of consensus represents a significant gap which may impact development and regulatory acceptance of freeze-dried pharmaceuticals and biopharmaceuticals. Review of the literature demonstrates that the temperature dependence of degradation rate constants in lyophiles can be represented by the Arrhenius equation in most cases. In some instances there is a break in the Arrhenius plot around the glass transition temperature or a related characteristic temperature. The majority of the activation energies (Ea), which are reported for various degradation pathways in lyophiles, falls in the range of 8 to 25 kcal/mol. The degradation Ea values for lyophiles are compared with the Ea for relaxation processes and diffusion in glasses, as wells as solution chemical reactions. Collectively, analysis of the literature demonstrates that the Arrhenius equation represents a reasonable empirical tool for analysis, presentation, and extrapolation of stability data for lyophiles, provided that specific conditions are met.

Vial Breakage in Lyophilization- Case Studies from Commercial Manufacturing and Laboratory Studies.

Vial breakage during lyophilization reduces yield and can lead to product contamination with glass particulates, personnel interventions during manufacturing and damage to equipment. We present case studies of full-scale commercial lyophilization operations and small-scale laboratory lyophilization studies to understand and mitigate the sources of vial breakage for sterile injectable products. In the first case study, changes to the lyophilization cycle caused the breakage of 11% of the vials. Breakage rates were higher on the top than the bottom shelves and higher for vials on the edges of the shelves than for center vials. Laboratory strain gauge and process parameter ranging studies confirmed the breakage mechanism to be thermal expansion of the frozen plug early in primary drying, the temperature of which was increased by the cycle changes. We postulate that residual heat from steam sterilization coupled with edge effects drove the breakage patterns. In another case study, we reduced breakage from 3.5% to 0.4% in commercial production by changing the freezing temperature from -45°C to -25°C. Laboratory strain gauge studies confirmed reduced incidence and severity of "break-free" / "plugging-off," which occurs when the frozen plug abruptly detaches from the vial sidewalls as it is cooled well below Tg'. The final case study is a "breakage challenge" study in the lab using higher fill volumes and aggressive drying to challenge the strength of vials. For borosilicate vials, breakage rates were dramatically higher after washing and tunnel depyrogenation in commercial manufacturing compared to vials that were used as received. Corning Valor® vials remained unbreakable even after processing. Tin oxide external coating provided borosilicate vials significant protection against damage from vial processing. These case studies illuminate vial breakage mechanisms, show how small-scale strain gauge and breakage challenge studies can be used to nearly eliminate vial breakage during full-scale commercial lyophilization.

Stress Factors in Protein Drug Product Manufacturing and Their Impact on Product Quality.

Injectable protein-based medicinal products (drug products, or DPs) must be produced by using sterile manufacturing processes to ensure product safety. In DP manufacturing the protein drug substance, in a suitable final formulation, is combined with the desired primary packaging (e.g., syringe, cartridge, or vial) that guarantees product integrity and enables transportation, storage, handling and clinical administration. The protein DP is exposed to several stress conditions during each of the unit operations in DP manufacturing, some of which can be detrimental to product quality. For example, particles, aggregates and chemically-modified proteins can form during manufacturing, and excessive amounts of these undesired variants might cause an impact on potency or immunogenicity. Therefore, DP manufacturing process development should include identification of critical quality attributes (CQAs) and comprehensive risk assessment of potential protein modifications in process steps, and the relevant steps must be characterized and controlled. In this commentary article we focus on the major unit operations in protein DP manufacturing, and critically evaluate each process step for stress factors involved and their potential effects on DP CQAs. Moreover, we discuss the current industry trends for risk mitigation, process control including analytical monitoring, and recommendations for formulation and process development studies, including scaled-down runs.

Dry powder measles vaccine: particle deposition, virus replication, and immune response in cotton rats following inhalation.

A stable and high potency dry powder measles vaccine with a particle size distribution suitable for inhalation was manufactured by CO(2)-Assisted Nebulization with a Bubble Dryer(®) (CAN-BD) process from bulk liquid Edmonston-Zagreb live attenuated measles virus vaccine supplied by the Serum Institute of India. A novel dry powder inhaler, the PuffHaler(®) was adapted for use in evaluating the utility of cotton rats to study the vaccine deposition, vaccine virus replication, and immune response following inhalation of the dry powder measles vaccine. Vaccine deposition in the lungs of cotton rats and subsequent viral replication was detected by measles-specific RT-PCR, and viral replication was confined to the lungs. Inhalation delivery resulted in an immune response comparable to that following injection. The cotton rat model is useful for evaluating new measles vaccine formulations and delivery devices.