Virus-like particles (VLPs) are bioengineered protein complexes that can serve as prophylactic vaccines due to favorable immunological characteristics like size, repetitive surface geometry and ability to induce both innate and adaptive immune responses, without being infectious. Large-scale manufacturing of VLPs presents some interesting and unique challenges associated with removal of refractory contaminants to attain high product purity, improvement in structural homogeneity and colloidal stability. Recent advancements in production and purification of VLP-based vaccines, such as application of monolithic multicolumn chromatography and inline concentration and diafiltration, have set a stage for implementation of continuous bioprocessing for commercial manufacturing of VLPs. The benefits of continuous bioprocessing have been well demonstrated for biotherapeutics, particularly monoclonal antibodies and small peptides. With the growing demand for affordable vaccines, the biopharmaceutical industry has shown increasing interest in establishing end-to-end continuous platforms. This article reviews major developments that have occurred in continuous processing for the manufacturing of VLPs. The major problems inherent in transitions from batch to continuous processing are also discussed, along with potential strategies to overcome the challenges.

Active pharmaceutical ingredients (APIs) typically consist of solid therapeutic particles that may acquire electrostatic charge during milling and grinding operations. This may result in the agglomeration of particles, thereby reducing the flowability and affecting the homogeneity of the drug formulation. Electrostatic charge build-up may also lead to fire explosions. To avoid charge build-up, APIs are often coated with polymers. In this paper, atomic layer deposition (ALD) using metal oxides such as Al2O3 and TiO2 on APIs, namely, palbociclib and pazopanib HCl, has been utilized to demonstrate a uniform coating that results in a significant reduction in the surface charge of the drug particles. Kelvin probe force microscopy (KPFM) shows a 4-fold decrease in the surface contact potential of uncoated pazopanib HCl (2.3 V) to 0.52 and 0.82 V in TiO2-and Al2O3-coated APIs, respectively. Also, the ζ potential indicated a 4-fold decrease in the surface charge on coating pazopanib HCl, i.e., from −32.9 mV to −7.51 and −8.51 mV in Al2O3 and TiO2, respectively. Surface morphology, thermal stability, dissolution studies, and cytotoxicity of the drug particles after coating were also examined. Thermal analysis indicated no change in the melting temperature (T m) after coating. ALD coating was found to be uniform and conformal as observed in images obtained from scanning electron microscopy (SEM) and scanning electron microscopy–energy-dispersive X-ray spectroscopy (SEM–EDS). The rate of dissolution was found to be delayed by the coating, and thus ALD offers slower drug release. Coating APIs with TiO2 and Al2O3 did not induce statistically significant cytotoxicity compared to the uncoated samples. The results presented in this study demonstrate that ALD coating can be used to reduce surface charge build-up and enhance the bulk properties of the drug particles without affecting their physicochemical properties.

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