The Science is There: Key Considerations for Stabilizing Viral Vector-Based Covid-19 Vaccines.

Once Covid-19 vaccines become available, 5-10 billion vaccine doses should be globally distributed, stored and administered. In this commentary, we discuss how this enormous challenge could be addressed for viral vector-based Covid-19 vaccines by learning from the wealth of formulation development experience gained over the years on stability issues related to live attenuated virus vaccines and viral vector vaccines for other diseases. This experience has led -over time- to major improvements on storage temperature, shelf-life and in-use stability requirements. First, we will cover work on 'classical' live attenuated virus vaccines as well as replication competent viral vector vaccines. Subsequently, we address replication deficient viral vector vaccines. Freeze drying and storage at 2-8 °C with a shelf life of years has become the norm. In the case of pandemics with incredibly high and urgent product demands, however, the desire for rapid and convenient distribution chains combined with short end-user storage times require that liquid formulations with shelf lives of months stored at 2-8 °C be considered. In confronting this "perfect storm" of Covid-19 vaccine stability challenges, understanding the many lessons learned from decades of development and manufacturing of live virus-based vaccines is the shortest path for finding promising and rapid solutions.

Formulation of Cell-Based Medicinal Products: A Question of Life or Death?

The formulation of cell-based medicinal products (CBMPs) poses major challenges because of their complexity, heterogeneity, interaction with their environment (e.g., the formulation buffer, interfaces), and susceptibility to degradation. These challenges can be quality, safety, and efficacy related. In this commentary we discuss the current status in formulation strategies of off-the-shelf and non-off-the-shelf (patient-specific) CBMPs and highlight advantages and disadvantages of each strategy. Analytical tools for the characterization and stability assessment of CBMP formulations are addressed as well. Finally, we discuss unmet needs and make some recommendations regarding the formulation of CBMPs.

Shifting Paradigms Revisited: Biotechnology and the Pharmaceutical Sciences.

In 2003, Crommelin et al. published an article titled: "Shifting paradigms: biopharmaceuticals versus low molecular weight drugs" (https://doi.org/10.1016/S0378-5173(03)00376-4). In the present commentary, 16 years later, we discuss pharmaceutically relevant aspects of the evolution of biologics since then. First, we discuss the increasing repertoire of biologics, in particular, the rapidly growing monoclonal antibody family and the advent of advanced therapy medicinal products. Next, we discuss trends in formulation and characterization as well as summarize our current insights into immunogenicity of biologics. We spend a separate section on new product(ion) paradigms for biologics, such as cell-free production systems, production of advanced therapy medicinal products, and downscaled production approaches. Furthermore, we share our views on issues related to reaching the patient, including routes and techniques of administration, alternative development models for affordable biologics, biosimilars, and handling of biologics. In the concluding section, we outline outstanding issues and make some suggestions for resolving those.

Potency assay development for cellular therapy products: an ISCT review of the requirements and experiences in the industry.

The evaluation of potency plays a key role in defining the quality of cellular therapy products (CTPs). Potency can be defined as a quantitative measure of relevant biologic function based on the attributes that are linked to relevant biologic properties. To achieve an adequate assessment of CTP potency, appropriate in vitro or in vivo laboratory assays and properly controlled clinical data need to be created. The primary objective of a potency assay is to provide a mechanism by which the manufacturing process and the final product for batch release are scrutinized for quality, consistency and stability. A potency assay also provides the basis for comparability assessment after process changes, such as scale-up, site transfer and new starting materials (e.g., a new donor). Potency assays should be in place for early clinical development, and validated assays are required for pivotal clinical trials. Potency is based on the individual characteristics of each individual CTP, and the adequacy of potency assays will be evaluated on a case-by-case basis by regulatory agencies. We provide an overview of the expectations and challenges in development of potency assays specific for CTPs; several real-life experiences from the cellular therapy industry are presented as illustrations. The key observation and message is that aggressive early investment in a solid potency evaluation strategy can greatly enhance eventual CTP deployment because it can mitigate the risk of costly product failure in late-stage development.