Quality-by-Design for the safe development of medical devices containing nanomaterials. A study case in photodynamic therapy

Présentation PosterInternational audienceBackground. According to the new medical device regulation (MDR 2017/745), devices employing advanced materials containing nanomaterials will be classified as class III and will have to undergo (re-)assessment of risks. To that aim, the Quality-by-Design approach, as defined in ICH Q8-Q11 (QbD), is indisputably accepted and strongly recommended by the FDA and EMA for risk assessment during drug development. Some papers have emphasized the possible implementation of QbD in the medical device industry [1]. Nevertheless, to date no real and effective adaptation of this risk-based quality management approach has been adapted to biomedical devices manufacturing [2]. Objectives. Our goal is to develop both a new QbD paradigm and a web-based tool devoted to the safe development of class-III medical devices containing nanomaterials. This objective is pursued in the context of the European H2020 project TBMED (An Open Innovation test bed for the development of high-risk medical devices).Methods. A six-step QbD approach is proposed. The first four stages are devoted to the preclinical development while the next two steps concern the industrial implementation. Three categories of risk-assessment methods are used at different development steps: failure mode and effects analysis based on prior knowledge, statistical designs of experiments and Bayesian inference. To assess its applicability, we applied the integrated QbD approach to the development of a new medical device devoted to the realtime control of light during photodynamic therapy using nanoparticle-based photosensitizers. Results. The new SaaS platform, entitled “Nanologic”, is available at: (www.i-nano.eu). Four key documents for regulatory agencies are established during the preclinical study: the target product profile, the list of critical quality attributes (quality/safety descriptors), the list of critical material attributes and process parameters (risk factors associated with the design and production phases) and the design space: a key concept of risk assessment in QbD.Conclusion. We show how the QbD best practices can be adapted to the development of medical devices containing nanomaterials. Moreover, new questions still have to be investigated such as the solutions to be developed to better predict risks associated with the clinical proof of concept

Quality-by-Design for the safe development of medical devices containing nanomaterials. A study case in photodynamic therapy

Présentation PosterInternational audienceBackground. According to the new medical device regulation (MDR 2017/745), devices employing advanced materials containing nanomaterials will be classified as class III and will have to undergo (re-)assessment of risks. To that aim, the Quality-by-Design approach, as defined in ICH Q8-Q11 (QbD), is indisputably accepted and strongly recommended by the FDA and EMA for risk assessment during drug development. Some papers have emphasized the possible implementation of QbD in the medical device industry [1]. Nevertheless, to date no real and effective adaptation of this risk-based quality management approach has been adapted to biomedical devices manufacturing [2]. Objectives. Our goal is to develop both a new QbD paradigm and a web-based tool devoted to the safe development of class-III medical devices containing nanomaterials. This objective is pursued in the context of the European H2020 project TBMED (An Open Innovation test bed for the development of high-risk medical devices).Methods. A six-step QbD approach is proposed. The first four stages are devoted to the preclinical development while the next two steps concern the industrial implementation. Three categories of risk-assessment methods are used at different development steps: failure mode and effects analysis based on prior knowledge, statistical designs of experiments and Bayesian inference. To assess its applicability, we applied the integrated QbD approach to the development of a new medical device devoted to the realtime control of light during photodynamic therapy using nanoparticle-based photosensitizers. Results. The new SaaS platform, entitled “Nanologic”, is available at: (www.i-nano.eu). Four key documents for regulatory agencies are established during the preclinical study: the target product profile, the list of critical quality attributes (quality/safety descriptors), the list of critical material attributes and process parameters (risk factors associated with the design and production phases) and the design space: a key concept of risk assessment in QbD.Conclusion. We show how the QbD best practices can be adapted to the development of medical devices containing nanomaterials. Moreover, new questions still have to be investigated such as the solutions to be developed to better predict risks associated with the clinical proof of concept

An Ultra-Thin Polymer Coating for the Tethering of Adenoviral Vector to the Surface of Coronary Stents

Our group has previously demonstrated stent-based gene delivery with either viral or plasmid vectors. However, these previous studies utilized bulky PLGA or collagen stent coatings, known to cause inflammatory reactions in stented arteries. In the present experiments we successfully attached adenoviruses either directly, or via anti-adenovirus antibodies to the steel surface of stents using chemical coordination with biphosphonates

‘Living a life less ordinary’: exploring the experiences of Australian men who have acquired HIV overseas

Background: Increasing international mobility has led to a growth of cross-border HIV transmission around the world. In Australia, increasing rates of HIV infections acquired overseas have been reported, particularly among men. This qualitative study explored experiences and risk perceptions of 14 Australian men who acquired HIV while living or travelling overseas from the year 2000. Methods: Symbolic interaction provided the study’s theoretical perspective and analytical framework. Australian men living with HIV who were aged 18 years and older, believed they had acquired their infection while working or travelling overseas during or after the year 2000, and were diagnosed from 2003 onwards were eligible to participate. A semistructured interview schedule was developed and tested for content validity with the study reference group. Analysis was conducted using an adapted form of grounded theory to form the basis for the development of the experiences domains. Results: Analysis produced four domains of experience: (1) a fantasy realised, (2) escaping and finding a new self or life, (3) living a life less ordinary and (4) living local but still an outsider. The description of the four experience domains highlights how risk generally, particularly sexual risk, did or did not feature in these men’s understanding of their experiences. Conclusion: Perceptions and experiences of long-term travel played a decisive role for men who acquired HIV when travelling overseas. Appealing to desired experiences such as connection to local culture or sustaining a new or adventurous life may provide important implications for guiding health promotion programs and policy

Somatic mutations activating STAT3 in human inflammatory hepatocellular adenomas

Somatic STAT3 mutations present in a subset of inflammatory hepatocellular adenomas result in the generation of constitutively active STAT3 proteins that homodimerize independently of IL-6 stimulation

Geospatial Resolution of Human and Bacterial Diversity with City-Scale Metagenomics

The panoply of microorganisms and other species present in our environment influence human health and disease, especially in cities, but have not been profiled with metagenomics at a city-wide scale. We sequenced DNA from surfaces across the entire New York City (NYC) subway system, the Gowanus Canal, and public parks. Nearly half of the DNA (48%) does not match any known organism; identified organisms spanned 1,688 bacterial, viral, archaeal, and eukaryotic taxa, which were enriched for harmless genera associated with skin (e.g., Acinetobacter). Predicted ancestry of human DNA left on subway surfaces can recapitulate U.S. Census demographic data, and bacterial signatures can reveal a station’s history, such as marine-associated bacteria in a hurricane-flooded station. Some evidence of pathogens was found (Bacillus anthracis), but a lack of reported cases in NYC suggests that the pathogens represent a normal, urban microbiome. This baseline metagenomic map of NYC could help long-term disease surveillance, bioterrorism threat mitigation, and health management in the built environment of citie

Vitamin C: Intravenous Use by Complementary and Alternative Medicine Practitioners and Adverse Effects

Background: Anecdotal information and case reports suggest that intravenously administered vitamin C is used by Complementary and Alternate Medicine (CAM) practitioners. The scale of such use in the U.S. and associated side effects are unknown. Methods and Findings: We surveyed attendees at annual CAM Conferences in 2006 and 2008, and determined sales of intravenous vitamin C by major U.S. manufacturers/distributors. We also queried practitioners for side effects, compiled published cases, and analyzed FDA’s Adverse Events Database. Of 199 survey respondents (out of 550), 172 practitioners administered IV vitamin C to 11,233 patients in 2006 and 8876 patients in 2008. Average dose was 28 grams every 4 days, with 22 total treatments per patient. Estimated yearly doses used (as 25g/50ml vials) were 318,539 in 2006 and 354,647 in 2008. Manufacturers ’ yearly sales were 750,000 and 855,000 vials, respectively. Common reasons for treatment included infection, cancer, and fatigue. Of 9,328 patients for whom data is available, 101 had side effects, mostly minor, including lethargy/fatigue in 59 patients, change in mental status in 21 patients and vein irritation/phlebitis in 6 patients. Publications documented serious adverse events, including 2 deaths in patients known to be at risk for IV vitamin C. Due to confounding causes, the FDA Adverse Events Database was uninformative. Total numbers of patients treated in the US with high dose vitamin C cannot be accurately estimated from this study

The Metagenomics and Metadesign of the Subways and Urban Biomes (MetaSUB) International Consortium inaugural meeting report

The Metagenomics and Metadesign of the Subways and Urban Biomes (MetaSUB) International Consortium is a novel, interdisciplinary initiative comprised of experts across many fields, including genomics, data analysis, engineering, public health, and architecture. The ultimate goal of the MetaSUB Consortium is to improve city utilization and planning through the detection, measurement, and design of metagenomics within urban environments. Although continual measures occur for temperature, air pressure, weather, and human activity, including longitudinal, cross-kingdom ecosystem dynamics can alter and improve the design of cities. The MetaSUB Consortium is aiding these efforts by developing and testing metagenomic methods and standards, including optimized methods for sample collection, DNA/RNA isolation, taxa characterization, and data visualization. The data produced by the consortium can aid city planners, public health officials, and architectural designers. In addition, the study will continue to lead to the discovery of new species, global maps of antimicrobial resistance (AMR) markers, and novel biosynthetic gene clusters (BGCs). Finally, we note that engineered metagenomic ecosystems can help enable more responsive, safer, and quantified cities