Emerging Challenges and Innovations in Surfactant-mediated Stabilization of Biologic Formulations.

Biologics may be subjected to various destabilizing conditions during manufacturing, transportation, storage, and use. Therefore, biologics must be appropriately formulated to meet their desired quality target product profiles. In the formulations of protein-based biologics, one critical component is surfactant. Polysorbate 80 and Polysorbate 20 remain the most commonly used surfactants. Surfactants can stabilize proteins through different mechanisms and help the proteins withstand destabilization stresses. However, the challenges associated with surfactants, for instance, impurities, degradation, and potential triggering of adverse immune responses, have been encountered. Therefore, there are continued efforts to develop novel surfactants to overcome these challenges associated with traditional surfactants. Meanwhile, surfactants have also found their use in formulations of newer and novel modalities, namely, antibody-drug conjugates, bispecific antibodies, and adeno-associated viruses (AAV). This review provides an updated in-depth discussion of surfactants in the above-mentioned areas, namely mechanism of action of surfactants, a critical review of challenges with surfactants and current mitigation approaches, and emerging technologies to develop novel surfactants. In addition, gaps, current mitigations, and future directions have been presented to trigger further discussion and research to facilitate the use and development of novel surfactants.

Stress Factors in Primary Packaging, Transportation and Handling of Protein Drug Products and Their Impact on Product Quality.

Protein-based biologic drugs encounter a variety of stress factors during drug substance (DS) and drug product (DP) manufacturing, and the subsequent steps that result in clinical administration by the end user. This article is the third in a series of commentaries on these stress factors and their effects on biotherapeutics. It focuses on assessing the potential negative impact from primary packaging, transportation, and handling on the quality of the DP. The risk factors include ingress of hazardous materials such as oxidizing residuals from the sterilization process, delamination- or rubber stopper-derived particles, silicone oil droplets, and leachables into the formulation, as well as surface interactions between the protein and packaging materials, all of which may cause protein degradation. The type of primary packaging container used (such as vials and prefilled syringes) may substantially influence the impact of transportation and handling stresses on DP Critical Quality Attributes (CQAs). Mitigations via process development and robustness studies as well as control strategies for DP CQAs are discussed, along with current industry best practices for scale-down and in-use stability studies. We conclude that more research is needed on postproduction transportation and handling practices and their implications for protein DP quality.

The Confluence of Innovation in Therapeutics and Regulation: Recent CMC Considerations.

The field of human therapeutics has expanded tremendously from small molecules to complex biological modalities, and this trend has accelerated in the last two decades with a greater diversity in the types and applications of novel modalities, accompanied by increasing sophistication in drug delivery technology. These innovations have led to a corresponding increase in the number of therapies seeking regulatory approval, and as the industry continues to evolve regulations will need to adapt to the ever-changing landscape. The growth in this field thus represents a challenge for regulatory authorities as well as for sponsors. This review provides a brief description of novel biologics, including innovative antibody therapeutics, genetic modification technologies, new developments in vaccines, and multifunctional modalities. It also describes a few pertinent drug delivery mechanisms such as nanoparticles, liposomes, coformulation, recombinant human hyaluronidase for subcutaneous delivery, pulmonary delivery, and 3D printing. In addition, it provides an overview of the current CMC regulatory challenges and discusses potential methods of accelerating regulatory mechanisms for more efficient approvals. Finally, we look at the future of biotherapeutics and emphasize the need to bring these modalities to the forefront of patient care from a global perspective as effectively as possible.

Characterization of Subvisible Particles in Biotherapeutic Prefilled Syringes: The Role of Polysorbate and Protein on the Formation of Silicone Oil and Protein Subvisible Particles After Drop Shock.

Subvisible particles (SbVPs) are a critical quality attribute for biotherapeutics. Particle content in prefilled syringes (PFSs) of a biotherapeutic can include protein particles and silicone oil particles (SiOP). Here, a real-world protein therapeutic PFS shows that although polysorbate is effective in preventing protein particle formation, it also leads to the formation of SiOP. PFSs of protein and buffer formulations in the presence and absence of polysorbate are subjected to a drop shock to generate SbVP and the effect of polysorbate and protein in generating SbVP is investigated. Particle characterization by light obscuration and flow imaging shows that polysorbate prevents protein particle formation as intended, but the presence of polysorbate substantially increases the formation of SiOP. The protein itself also acts as a surfactant and leads to increased SiOP, but to a lesser degree compared to polysorbate. In a separate companion study by Joh et al., the risk of immunogenicity was assessed using in vivo and in vitro models. Flow imaging distinguishes between SiOP and protein particles and enables risk assessment of the natures of different SbVP in PFSs.

Silicone Oil Particles in Prefilled Syringes With Human Monoclonal Antibody, Representative of Real-World Drug Products, Did Not Increase Immunogenicity in In Vivo and In Vitro Model Systems.

Silicone oil is a lubricant for prefilled syringes (PFS), a common primary container for biotherapeutics. Silicone oil particles (SiOP) shed from PFS are a concern for patients due to their potential for increased immunogenicity and therefore also of regulatory concern. To address the safety concern in a context of manufacturing and distribution of drug product (DP), SiOP was increased (up to ∼25,000 particles/mL) in PFS filled with mAb1, a fully human antibody drug, by simulated handling of DP mimicked by drop shock. These samples are characterized in a companion report (Jiao N et al. J Pharm Sci. 2020). The risk of immunogenicity was then assessed using in vitro and in vivo immune model systems. The impact of a common DP excipient, polysorbate 80, on both the formation and biological consequences of SiOP was also tested. SiOP was found associated with (1) minimal cytokine secretion from human peripheral blood mononuclear cells, (2) no response in cell lines that report NF-κB/AP-1 signaling, and (3) no antidrug antibodies or significant cytokine production in transgenic Xeno-het mice, whether or not mAb1 or polysorbate 80 was present. These results suggest that SiOP in mAb1, representative of real-world DP in PFS, poses no increased risk of immunogenicity.