Stability of Protein Pharmaceuticals: Recent Advances.

There have been significant advances in the formulation and stabilization of proteins in the liquid state over the past years since our previous review. Our mechanistic understanding of protein-excipient interactions has increased, allowing one to develop formulations in a more rational fashion. The field has moved towards more complex and challenging formulations, such as high concentration formulations to allow for subcutaneous administration and co-formulation.

Data-driven dynamical coarse-graining for condensed matter systems.

Simulations of condensed matter systems often focus on the dynamics of a few distinguished components but require integrating the full system. A prime example is a molecular dynamics simulation of a (macro)molecule in a solution, where the molecule(s) and the solvent dynamics need to be integrated, rendering the simulations computationally costly and often unfeasible for physically/biologically relevant time scales. Standard coarse graining approaches can reproduce equilibrium distributions and structural features but do not properly include the dynamics.

The Storage and In-Use Stability of mRNA Vaccines and Therapeutics: Not A Cold Case.

The remarkable impact of mRNA vaccines on mitigating disease and improving public health has been amply demonstrated during the COVID-19 pandemic. Many new mRNA-based vaccine and therapeutic candidates are in development, yet the current reality of their stability limitations requires their frozen storage. Numerous challenges remain to improve formulated mRNA stability and enable refrigerator storage, and this review provides an update on developments to tackle this multi-faceted stability challenge.

Applying lessons learned from nanomedicines to understand rare hypersensitivity reactions to mRNA-based SARS-CoV-2 vaccines.

After over a billion of vaccinations with messenger RNA-lipid nanoparticle (mRNA-LNP) based SARS-CoV-2 vaccines, anaphylaxis and other manifestations of hypersensitivity can be considered as very rare adverse events. Although current recommendations include avoiding a second dose in those with first-dose anaphylaxis, the underlying mechanisms are unknown; therefore, the risk of a future reaction cannot be predicted. Given how important new mRNA constructs will be to address the emergence of new viral variants and viruses, there is an urgent need for clinical approaches that would allow a safe repeated immunization of high-risk individuals and for reliable predictive tools of adverse reactions to mRNA vaccines.

Ongoing Challenges to Develop High Concentration Monoclonal Antibody-based Formulations for Subcutaneous Administration: Quo Vadis?

Although many subcutaneously (s.c.) delivered, high-concentration antibody formulations (HCAF) have received regulatory approval and are widely used commercially, formulation scientists are still presented with many ongoing challenges during HCAF development with new mAb and mAb-based candidates.

Uncertainty quantification and sensitivity analysis of COVID-19 exit strategies in an individual-based transmission model.

Many countries are currently dealing with the COVID-19 epidemic and are searching for an exit strategy such that life in society can return to normal. To support this search, computational models are used to predict the spread of the virus and to assess the efficacy of policy measures before actual implementation. The model output has to be interpreted carefully though, as computational models are subject to uncertainties.

mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability.

A drawback of the current mRNA-lipid nanoparticle (LNP) COVID-19 vaccines is that they have to be stored at (ultra)low temperatures. Understanding the root cause of the instability of these vaccines may help to rationally improve mRNA-LNP product stability and thereby ease the temperature conditions for storage. In this review we discuss proposed structures of mRNA-LNPs, factors that impact mRNA-LNP stability and strategies to optimize mRNA-LNP product stability.

Assessing uncertainties from physical parameters and modelling choices in an atmospheric large eddy simulation model.

In this study, we investigate uncertainties in a large eddy simulation of the atmosphere, employing modern uncertainty quantification methods that have hardly been used yet in this context. When analysing the uncertainty of model results, one can distinguish between uncertainty related to physical parameters whose values are not exactly known, and uncertainty related to modelling choices such as the selection of numerical discretization methods, of the spatial domain size and resolution, and the use of different model formulations. While the former kind is commonly studied e.

The impact of uncertainty on predictions of the CovidSim epidemiological code.

Epidemiological modelling has assisted in identifying interventions that reduce the impact of COVID-19. The UK government relied, in part, on the CovidSim model to guide its policy to contain the rapid spread of the COVID-19 pandemic during March and April 2020; however, CovidSim contains several sources of uncertainty that affect the quality of its predictions: parametric uncertainty, model structure uncertainty and scenario uncertainty. Here we report on parametric sensitivity analysis and uncertainty quantification of the code.

Addressing the Cold Reality of mRNA Vaccine Stability.

As mRNA vaccines became the frontrunners in late-stage clinical trials to fight the COVID-19 pandemic, challenges surrounding their formulation and stability became readily apparent. In this commentary, we first describe company proposals, based on available public information, for the (frozen) storage of mRNA vaccine drug products across the vaccine supply chain. We then review the literature on the pharmaceutical stability of mRNA vaccine candidates, including attempts to improve their stability, analytical techniques to monitor their stability, and regulatory guidelines covering product characterization and storage stability.

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.

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.

The role of liposomes in clinical nanomedicine development. What now? Now what?

The rapid rise in interest in 'nanomedicines' in the academic world over the last twenty years and the claims of success led to calls for reflection. The main body of text of this Commentary will be on answering the question: 'where to go with nanomedicines'? Research priorities for the future will be outlined based on experience with the most successful nanomedicines family within the broad field of nanomedicine so far: liposomes. An analysis of currently clinically tested, approved and marketed liposome-drug combinations provides these insights.

Identification of Formaldehyde-Induced Modifications in Diphtheria Toxin.

Diphtheria toxoid is produced by detoxification of diphtheria toxin with formaldehyde. This study was performed to elucidate the chemical nature and location of formaldehyde-induced modifications in diphtheria toxoid. Diphtheria toxin was chemically modified using 4 different reactions with the following reagents: (1) formaldehyde and NaCNBH, (2) formaldehyde, (3) formaldehyde and NaCNBH followed by formaldehyde and glycine, and (4) formaldehyde and glycine.

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.

Report of the AAPS Guidance Forum on the FDA Draft Guidance for Industry: "Drug Products, Including Biological Products, that Contain Nanomaterials".

To guide developers of innovative and generic drug products that contain nanomaterials, the U.S. Food and Drug Administration issued the draft guidance for industry titled: "Drug Products, Including Biological Products, that Contain Nanomaterials" in December 2017.

Rare event simulation for steady-state probabilities via recurrency cycles.

We develop a new algorithm for the estimation of rare event probabilities associated with the steady-state of a Markov stochastic process with continuous state space R and discrete time steps (i.e., a discrete-time R-valued Markov chain).

Quantifying Data Dependencies with Rényi Mutual Information and Minimum Spanning Trees.

In this study, we present a novel method for quantifying dependencies in multivariate datasets, based on estimating the Rényi mutual information by minimum spanning trees (MSTs). The extent to which random variables are dependent is an important question, e.g.

Postproduction Handling and Administration of Protein Pharmaceuticals and Potential Instability Issues.

The safety and efficacy of protein pharmaceuticals depend not only on biological activity but also on purity levels. Impurities may be process related because of limitations in manufacturing or product related because of protein degradation occurring throughout the life history of a product. Although the pharmaceutical biotechnology industry has made great progress in improving bulk and drug product manufacturing as well as company-controlled storage and transportation conditions to minimize the level of degradation, there is less control over the many factors that may subsequently affect product quality after the protein pharmaceuticals are released and shipped by the manufacturer.

How to select a nanosimilar.

Nanomedicines in the class of nonbiological complex drugs (NBCDs) are becoming increasingly available. Up to 23 nanomedicines have been approved, and approximately 50 are in clinical development. Meanwhile, the first nanosimilars have entered the market through the generic approval pathway, but clinical differences have been observed.

Reflections on the Future of Pharmaceutical Public-Private Partnerships: From Input to Impact.

Public Private Partnerships (PPPs) are multiple stakeholder partnerships designed to improve research efficacy. We focus on PPPs in the biomedical/pharmaceutical field, which emerged as a logical result of the open innovation model. Originally, a typical PPP was based on an academic and an industrial pillar, with governmental or other third party funding as an incentive.

Equivalence of complex drug products: advances in and challenges for current regulatory frameworks.

Biotechnology and nanotechnology provide a growing number of innovator-driven complex drug products and their copy versions. Biologics exemplify one category of complex drugs, but there are also nonbiological complex drug products, including many nanomedicines, such as iron-carbohydrate complexes, drug-carrying liposomes or emulsions, and glatiramoids. In this white paper, which stems from a 1-day conference at the New York Academy of Sciences, we discuss regulatory frameworks in use worldwide (e.

Pharmacy preparations: Back in the limelight? Pharmacists make up your mind!

In this contribution to the theme issue recognizing prof. Florence's achievements as editor -in-chief of the Int. J.