Introduction: Several new biopharmaceutical dosage forms have developed over time, such as lyophilized vial, liquid vial, and liquid prefilled syringe formulations. This review summarizes major pharmaceutical dosage forms and their advantages, disadvantages, and countermeasures against the shortcomings of each formulation. The appropriate combination of active pharmaceutical ingredients, excipients, and containers should be selected for the safe and less burdensome administration to the patients. Finally, we note certain opinions on the future development of not only therapeutic proteins but also gene therapeutics.Areas covered: This review is to discuss the challenges of the development of dosage forms to improve pharmaceutical stability and how they can be overcome. Expert opinion: Silicone oil-free syringes are highly preferable for minimizing subvisible particles in the drug. It can be proposed that materials with less protein adsorption property are preferable for the suppression of protein aggregation. It is required to minimize adverse effects of biopharmaceuticals through proper quality control of the drug in a container, based on the understating of physicochemical stability of the protein in solution, the physicochemical properties of the container, and their combinations.

This study evaluated how differences in the surface properties of prefillable syringe barrels and in-solution sampling methods affect micron aggregates and protein adsorption levels. Three syringe types (glass barrel with silicone oil coating [GLS/SO+], glass barrel without silicone oil coating [GLS/SO-], and cyclo-olefin polymer [COP] barrel syringes) were tested with 3 therapeutic proteins (adalimumab, etanercept, and infliximab) using 2 sampling methods (aspiration or ejection). After quiescent incubation, solutions sampled by aspiration exhibited no significant change in micron aggregate concentration in any syringes, whereas those sampled by ejection exhibited increased micron aggregates in both GLS syringe types. Micron aggregate concentration in ejected solutions generally increased with increasing density of adsorbed proteins. Notably, COP syringes contained the lowest micron aggregate concentrations, which were independent of the sampling method. Correspondingly, the adsorbed protein density on COP syringes was the lowest at 1-2 mg/m, which was much less compared with that on GLS syringes and was calculated to be equivalent to only 1-2 protein layers, as visually confirmed by high-speed atomic force microscopy. These data indicate that low-adsorption prefillable syringes should be used for therapeutic proteins because protein aggregate concentration in the ejected solution is elevated by increased protein adsorption to the syringe surface.

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In the past, analysis of micron-sized (>1.0 μm) aggregates of therapeutic proteins has been limited to light obscuration (LO), and appropriate quantitative methods of evaluating protein aggregates need to be developed. Recently, novel methods with enhanced reliability and sensitivity, such as nanoparticle tracking analysis (NTA), resonant mass measurement (RMM), and flow imaging (FI), have emerged. We have found that quantitative laser diffraction (qLD) is also effective for quantitative evaluation of protein aggregates over a wide size range. However, the different detection principles of the methods potentially lead to inconsistencies in results. This study aimed to compare particle size distributions and concentrations of protein aggregates using the orthogonal methods. Protein aggregates were generated by stirring an immunoglobulin solution. Serial dilutions of the aggregates stock were analyzed by RMM, FI, and qLD to obtain the particle size distribution and concentration using each method. In addition, size distribution of a protein aggregates solution was compared by RMM, NTA, FI, LO, and qLD. Both particle size distribution and concentration were in good agreement between RMM and qLD (0.3-2 μm) and between FI and qLD (2-20 μm). Thus, we concluded that qLD enables covering of the overlapping particle size range between RMM and FI.