Preventive Pharmacovigilance: timely and precise prevention of adverse events through person-level patient screening and dose-level product surveillance.

The goal of pharmacovigilance (PV) is to prevent adverse events (AEs) associated with drugs and vaccines. Current PV programs are of a reactive nature and rest entirely on data science, i.e.

Sedimentation behavior of quality and freeze-damaged aluminum-adjuvanted vaccines by NMR.

Vaccine sedimentation and resuspension are properties that vaccine makers use to characterize a suspension product during research and development as well as throughout the shelf life of the vaccine. Three vaccines with three different aluminum adjuvants and different antigens were selected and monitored over the course of sedimentation using water proton nuclear magnetic resonance (NMR) relaxometry. This simple method measured fully intact, single-dose vaccine vials and reported sedimentation profiles for each, which readily distinguished freeze-stressed vaccines from unstressed vaccines.

Making in silico predictive models for toxicology FAIR.

In silico predictive models for toxicology include quantitative structure-activity relationship (QSAR) and physiologically based kinetic (PBK) approaches to predict physico-chemical and ADME properties, toxicological effects and internal exposure. Such models are used to fill data gaps as part of chemical risk assessment. There is a growing need to ensure in silico predictive models for toxicology are available for use and that they are reproducible.

Retrospective analysis of the potential use of virtual control groups in preclinical toxicity assessment using the eTOX database.

Virtual Control Groups (VCGs) based on Historical Control Data (HCD) in preclinical toxicity testing have the potential to reduce animal usage. As a case study we retrospectively analyzed the impact of replacing Concurrent Control Groups (CCGs) with VCGs on the treatment-relatedness of 28 selected histopathological findings reported in either rat or dog in the eTOX database. We developed a novel methodology whereby statistical predictions of treatment-relatedness using either CCGs or VCGs of varying covariate similarity to CCGs were compared to designations from original toxicologist reports; and changes in agreement were used to quantify changes in study outcomes.

Statistical analysis of preclinical inter-species concordance of histopathological findings in the eTOX database.

Preclinical inter-species concordance can increase the predictivity of observations to the clinic, potentially reducing drug attrition caused by unforeseen adverse events. We quantified inter-species concordance of histopathological findings and target organ toxicities across four preclinical species in the eTOX database using likelihood ratios (LRs). This was done whilst only comparing findings between studies with similar compound exposure (Δ|C| ≤ 1 log-unit), repeat-dosing duration, and animals of the same sex.

Assessing Antigen-Adjuvant Complex Stability Against Physical Stresses By wNMR.

This study applies an emerging analytical technology, wNMR (water proton nuclear magnetic resonance), to assess the stability of aluminum adjuvants and antigen-adjuvant complexes against physical stresses, including gravitation, flow and freeze/thaw. Results from wNMR are verified by conventional analytical technologies, including static light scattering and microfluidic imaging. The results show that wNMR can quickly and noninvasively determine whether an aluminum adjuvant or antigen-adjuvant complex sample has been altered by physical stresses.

eTRANSAFE: Building a sustainable framework to share reproducible drug safety knowledge with the public domain.

Integrative drug safety research in translational health informatics has rapidly evolved and included data that are drawn in from many resources, combining diverse data that are either reused from (curated) repositories, or newly generated at source. Each resource is mandated by different sets of metadata rules that are imposed on the incoming data. Combination of the data cannot be readily achieved without interference of data stewardship and the top-down policy guidelines that supervise and inform the process for data combination to aid meaningful interpretation and analysis of such data.

Inspecting Insulin Products Using Water Proton NMR. I. Noninvasive vs Invasive Inspection.

Background: There is a clear need to transition from batch-level to vial/syringe/pen-level quality control of biologic drugs, such as insulin. This could be achieved only by noninvasive and quantitative inspection technologies that maintain the integrity of the drug product.

Methods: Four insulin products for patient self-injection presented as prefilled pens have been noninvasively and quantitatively inspected using the water proton NMR technology.

The eTRANSAFE Project on Translational Safety Assessment through Integrative Knowledge Management: Achievements and Perspectives.

eTRANSAFE is a research project funded within the Innovative Medicines Initiative (IMI), which aims at developing integrated databases and computational tools (the eTRANSAFE ToxHub) that support the translational safety assessment of new drugs by using legacy data provided by the pharmaceutical companies that participate in the project. The project objectives include the development of databases containing preclinical and clinical data, computational systems for translational analysis including tools for data query, analysis and visualization, as well as computational models to explain and predict drug safety events.

Guidelines for FAIR sharing of preclinical safety and off-target pharmacology data.

Pre-competitive data sharing can offer the pharmaceutical industry significant benefits in terms of reducing the time and costs involved in getting a new drug to market through more informed testing strategies and knowledge gained by pooling data. If sufficient data is shared and can be co-analyzed, then it can also offer the potential for reduced animal usage and improvements in the in silico prediction of toxicological effects. Data sharing benefits can be further enhanced by applying the FAIR Guiding Principles, reducing time spent curating, transforming and aggregating datasets and allowing more time for data mining and analysis.

Grand Challenges in Pharmaceutical Research Series: Ridding the Cold Chain for Biologics.

Biologics are complex pharmaceuticals that include formulated proteins, plasma products, vaccines, cell and gene therapy products, and biological tissues. These products are fragile and typically require cold chain for their delivery and storage. Delivering biologics, while maintaining the cold chain, whether standard (2°C to 8°C) or deepfreeze (as cold as -70°C), requires extensive infrastructure that is expensive to build and maintain.

Quality assurance at the point-of-care: Noninvasively detecting vaccine freezing variability using water proton NMR.

Aluminum-adjuvanted vaccines are freeze-sensitive products that require attentive cold chain adherence. Freeze/thaw events can be tested using "The World Health Organization Shake Test", a qualitative test whereby a vial from the batch suspected to have been frozen is checked to infer whether the whole batch has been frozen. In this paper, we present a noninvasive and quantitative method to detect whether a vial of liquid vaccine has experienced freeze/thaw using the water proton transverse relaxation rate by Nuclear Magnetic Resonance relaxometry (wNMR relaxometry).

Magnetic Resonance Relaxometry for Determination of Protein Concentration and Aggregation.

The water-proton signal, overwhelmingly considered a nuisance in nuclear magnetic resonance spectroscopy, is advantageously used as a tool to assess protein concentration and to detect protein aggregates in aqueous solutions. The protocols in this article describe use of the water-proton transverse relaxation rate to determine concentration and aggregate content in protein solutions. Detailed recommendations and description of the parameter settings and data processing ensure successful implementation of this technique, even by a user with limited experience in magnetic resonance relaxometry.

Flow Water Proton NMR: In-Line Process Analytical Technology for Continuous Biomanufacturing.

Continuous manufacturing of biologics is one of the priorities of the biopharmaceutical industry. However, its widespread implementation is hampered by a lack of noninvasive/nondestructive process analytical technology (PAT) systems capable of real-time in-line monitoring of product flow parameters, such as concentration and/or aggregate content. We have previously demonstrated that, under nonflow conditions, the water proton transverse relaxation rate, (HO), is sensitive to protein concentration and aggregate content in biopharmaceutical formulations.

Correction to: Nondestructive Quantitative Inspection of Drug Products Using Benchtop NMR Relaxometry-the Case of NovoMix® 30.

Typesetting error occurred and author corrections to the equations and text edits at the proofing stage were not incorporated in the published article. The original article has been corrected.

Curation and analysis of clinical pathology parameters and histopathologic findings from eTOXsys, a large database project (eTOX) for toxicologic studies.

Large data sharing projects amongst the pharmaceutical industry have the potential to generate new insights using data on a scale that has not been previously available. A retrospective analysis of the preclinical toxicology data collected as part of the eTOX project was conducted with the aim to provide background rates and treatment-related value analysis on both clinical pathology and histopathology datasets. Incorporated into this analysis was an extensive data consolidation task to standardise all data.

Nondestructive Quantitative Inspection of Drug Products Using Benchtop NMR Relaxometry-the Case of NovoMix® 30.

Batch-level inference-based quality control is the standard practice for drug products. However, rare drug product defects may be missed by batch-level statistical sampling, where a subset of vials in a batch is tested quantitatively but destructively. In 2013, a suspension insulin product, NovoLog® Mix 70/30 was recalled due to a manufacturing error, which resulted in insulin strength deviations up to 50% from the labeled value.

Monitoring dendrimer conformational transition using F and H O NMR.

The conformational transition of a fluorinated amphiphilic dendrimer is monitored by the H signal from water, alongside the F signal from the dendrimer. High-field NMR data (chemical shift δ, self-diffusion coefficient D, longitudinal relaxation rate R , and transverse relaxation rate R ) for both dendrimer ( F) and water ( H) match each other in detecting the conformational transition. Among all parameters for both nuclei, the water proton transverse-relaxation rate R ( H O) displays the highest relative scale of change upon conformational transition of the dendrimer.

Conformational transition of a non-associative fluorinated amphiphile in aqueous solution. II. Conformational transition supramolecular assembly.

Unlike many known amphiphiles, the fluorinated amphiphilic dendrimer studied in this work demonstrated a concentration-dependent conformational transition rather than micellization or assembly. Hydrophobic and hydrophilic interactions with water were suggested as the most probable driving force of this transition. This assumption was consistent with the observed F chemical shift changes of the dendrimer compared to a known micelle-forming fluorinated amphiphile.

Water proton NMR detection of amide hydrolysis and diglycine dimerization.

The transverse relaxation rate of water protons R2(1H2O) is found to be sensitive to amide hydrolysis and diglycine dimerization. The results demonstrate the feasibility of using R2(1H2O) as a diagnostic tool to detect chemical changes in aqueous solutions. Potential applications include drug product formulation and inspection.