EU MDR 2017/745 will reduce the Risk of Medical Devices. Does MDCG got it Right?

Under the new European Union Medical Device Regulation (EU MDR), framed by Medical Device Coordination Group (MDCG), for each device manufacturers must have a documented risk management plan, identify and analyse the known and foreseeable hazards, estimate and evaluate the associated risks and eliminate or control those risks. In contrast with the MDD, the new EU MDR contains an explicit obligation in the new Article 10 (2), that manufacturers establish, document, implement and maintain a system for risk management. The detailed requirements of which are listed in the new Annex I Chapter I. Compared to MDD there is more emphasis on Post Market Surveillance (PMS) activities with the inclusion of European Databank or European Database for Medical Devices (EUDAMED) and mandatory submission of Periodic Safety Update Report (PSUR) to all the actors in the possession with the medical devices. A poll conducted by Aegis Lifesciences Pvt. Ltd, Ahmedabad, India concludes that the relevant annexures and sections in MDR 2017/745 have more emphasis on PMS, Vigilance, PSUR, EUDAMED, tracking, Implantation card etc. that are directed in regard to the safety of the Medical Device.

14. Postmarketing Safety Experience With MenACWY-TT

Background MenACWY-TT (Nimenrix®), a quadrivalent meningococcal tetanus toxoid conjugate vaccine, was first licensed in 2012 and is available in 82 countries but not in the United States. MenACWY-TT is administered in infants as a 2 + 1 (6 weeks to < 6 months of age) or 1 + 1 (6 to < 12 months of age) schedule with the booster dose at 12 months of age, and from 12 months of age as a single dose. In addition to its widespread use to protect against meningococcal serogroups A, C, W, and Y, MenACWY-TT is a constituent of an investigational pentavalent meningococcal (MenABCWY) vaccine currently undergoing clinical development. Methods Using the MenACWY-TT Periodic Safety Update Report (PSUR) with format and content in accordance with Good Pharmacovigilance Practice Module VII and International Council for Harmonisation Guideline E2C, for data up to April 19, 2020, postmarketing safety experience with MenACWY-TT is considered. The PSUR data included herein are spontaneous adverse events (AEs) from the Pfizer safety database. AEs were coded by system organ class (SOC) and preferred term (PT) using MedDRA v.22.1J. Results The cumulative estimated exposure of MenACWY-TT was nearly 26 million doses, with the majority administered in 0- to 16-year-olds and in the Western European Union (Figure 1). Over the reporting period, 13,301 cumulative AEs occurred. The most common SOCs in the reporting period were general disorders and administration site conditions (n=5169; 39%); nervous system disorders (n=1986; 15%); injury, poisoning and procedural complications (n=1266; 10%); and gastrointestinal disorders (n=1031; 8%) (Figure 2). By PT, the most common AEs were pyrexia (n=1613; 12%), headache (n=738; 6%), and vaccination site pain (n=394; 3%) (Figure 3). Of the 3299 serious AEs reported, the most common were pyrexia (n=317; 10%) and headache (n=209; 6%). Conclusion Based on cumulative safety data in conjunction with existing efficacy and effectiveness data, the benefit-risk profile of MenACWY-TT remains favorable and is consistent with the safety profile of MenACWY-TT established in clinical studies. Disclosures Lidia Serra, MS, Pfizer Inc (Employee, Shareholder) Susan Mather, MD, Pfizer Inc (Employee, Shareholder) Cindy Burman, PharmD, Pfizer Inc (Employee, Shareholder) Chris Webber, MD, Pfizer (Employee, Shareholder)

MAP OF RADIOISOTOPE PRODUCTION AND BATAN RESEARCH REACTOR UTILIZATION

Currently, Indonesia through BATAN is operating three research reactors, namely the RSG-GAS reactor with the power of 30 MWt at Puspiptek south Tangerang (the first criticality in 1987), the TRIGA 2000 reactor with the power of 2 MW in Bandung which the first criticality in 1965 with the power of 250 kW, was increased to 1 MW in 1971, and further upgraded to 2 MW in 2000. Beside that, there is Kartini reactor with a power of 100 kW located in Yogyakarta (first criticality in 1979). These reactors are quite old, and in accordance with Bapeten regulations, have carried out the first periodic safety review, to obtain a reactor license for the next 10 years of operation. In line with this, one of BATAN's current national research programs is to increase the production of radioisotopes and radiopharmaceuticals, where reactors play a very important role in the production of certain isotopes. In tracing the data obtained from operational reports related to irradiation requests from reactor users, namely PTRR, PSTNT, and PT INUKI for radioisotope production, which has been carried out in the last 5 years, May 2015 until 25 August 2020, show that the irradiation request at RSG-GAS is still not optimal. In term of the utilization of RSG-GAS, it can still be optimized, which in this case needs to be balanced with post-irradiation processing capabilities. Meanwhile, from the results of tracing and data collection, it can be shown that at this time the reactors are still operating. The utilization activities of the reactors complement each other according to their age and facilities.

VERIFIKASI NILAI REAKTIVITAS LEBIH TERAS SETIMBANG RSG-GAS SETELAH 30 TAHUN BEROPERASI

Dalam rangka untuk menjamin keselamatan operasi reaktor RSG-GAS, harus dilakukan review terhadap parameter keselamatan operasi teras yang sering disebut dengan periodic safety review (PSR). Tujuannya adalah untuk melakukan verifikasi terhadap nilai parameter yang terkait dengan keselamatan yang ada di dalam Laporan Analisis Keselamatan (LAK), di mana aspek neutronik termasuk di dalamnya. Pada aspek ini dilakukan verifikasi terhadap reaktivitas lebih teras setimbang RSG-GAS setelah 30 tahun beroperasi melalui perhitungan menggunakan paket program WIMSD-5B/Batan-FUEL. Dari hasil perhitungan diperoleh nilai reaktivitas lebih pada teras setimbang RSG-GAS tanpa Xenon sebesar 7,7 %. Sedangkan nilai reaktivitas lebih hasil eksperimen teras RSG- GAS sebesar 7,4 %. Dari kedua nilai tersebut diperoleh hasil perhitungan verifikasi menunjukkan bahwa nilai perhitungan sesuai dengan nilai eksperimen dengan perbedaan 5 %.

Student Sensor Lab at Home: Safe Repurposing of Your Gadgets

The COVID-19 pandemic imposed various restrictions on the accessibility of conventional teaching laboratories. Enabling learning and experimenting at home became necessary to support the practical element of students’ learning. Unfortunately, it is not viable to provide or share a fully featured sensor lab to every student because of the prohibitive costs involved. Therefore, repurposing electronic devices that are common to students can bring about the sought-after practical learning experience without the hefty price tag. In distinction to the conventional lab instruments, however, consumer-grade devices are not designed for use with external sensors and/or electronic circuitry. They are not professionally maintained, do not undergo periodic safety tests, and are not calibrated. Nevertheless, nearly all modern computers, laptops, tablets or smartphones are equipped with high-quality audio inputs and outputs that can generate and record signals in the audible frequency range (20 Hz–20 kHz). Despite cutting off the direct currents completely, this range might be sufficient for working with a variety of sensors. In this presentation we look at the possibilities of making sure that such repurposing by design prevents any potential harm to the learner and to her or his personal equipment. These features seem essential for unsupervised lone experimenting and avoiding damage to expensive devices.

Pharmacovigilance: procedures for uniform assessment of periodic safety update reports and their implementation in national settings. Focus on analgesics

Pharmacovigilance activities are of vital importance for ensuring effective and safe medicinal products. In order to clarify to which extent marketing authorisation holders (MAHs) meet the requirements of the Law and the Directives related to this activities, we conducted a systematic search among the procedures submitted to the Bulgarian Drug Agency (BDA) related to the implementation of the decisions of the Pharmacovigilance Committee and the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) for a period of 6 years. The results of the study showed significant discrepancies between regulatory requirements and the behavior of the MAH at the national level. This could be a serious problem, as inadequate or late implementations of the PRAC (Pharmacovigilance Risk Assessment Committee)/CMDh/EC recommendations can lead to untimely informing of healthcare professionals and patients about potential safety concerns and risks related to the use of medicinal products.

Impact of Climate Change on EDF’s Nuclear Facilities: Climate Watch Approach

According to the Periodic Safety Review Process, the safety level is re-assessed every ten years, considering national and international operational feedback, evolution of knowledge and best available practices. Protection against natural hazards is part of this safety level re-assessment. In the current global change context, climate change impact has to be integrated in external natural hazards estimations, such as climatic hazards or external flooding. EDF has consequently implemented a climate watch approach. Undertaken approximately every 5 years, roughly in line with the publication of the assessment reports of the Intergovernmental Panel on Climate Change (IPCC) and with the update of safety licensing basis during Periodic Safety Reviews, this approach is intended to: - revisit the climatic hazards which present a plausible or certain upward trend, and could lead to an increased reference hazard level, - monitor the reach of target levels which should trigger a thorough analysis (concept of Major Climate Event) to ensure the robustness of the reference hazard level between two periodic reviews. This climate watch approach is developed in partnership with the scientific community and is based on the following activities: - compile and analyze datasets on hazards that are subject to changes with climate change (observed and modelled time series), - develop knowledge of associated climatic phenomena (models, projections). The application of this approach is presented in two steps: - the key implications of the last climate watch exercise carried out in 2015, which identified climatic hazards whose evolution is unfavorable and is plausible or certain for the sites of EDF NPPs: ○ High air and water temperatures (for the “heat wave” hazard) ○ Sea level (for the “external flooding” hazard for coastal or estuary sites) ○ Drought or « low flow » hazard for fluvial sites; - the results obtained for the 900 MW units, for which EDF started the 4th periodic safety review in 2019. Such an approach, which is closely linked to periodic reviews, ensures the robustness of nuclear power plants to the climatic hazards through the consideration of the updated hazard levels.

Protection of Nuclear Power Plants Against Natural Hazards: Consideration for EDF’s Nuclear Facilities of Decamillennial Events (WENRA RL T4.2)

Following the Fukushima Daiichi accident, the Western European Nuclear Regulators Association (WENRA) updated in 2014 the safety reference levels (SRL) for existing reactors, introducing a new chapter specific to natural hazards. In 2015, in preparation for the 4th periodic safety review of its 900 MW units, EDF aimed at meeting these new reference levels. While many of them were already satisfied for a long time by EDF (for example: Identification of natural hazards, Site specific natural hazard screening and assessment, Protection against design basis events), several of them were new objectives: - T4.2: The exceedance frequencies of design basis events shall be low enough to ensure a high degree of protection with respect to natural hazards. A common target value of frequency, not higher than 10−4 per annum, shall be used for each design basis event. Where it is not possible to calculate these probabilities with an acceptable degree of certainty, an event shall be chosen and justified to reach an equivalent level of safety. - T6.1: Events that are more severe than the design basis events shall be identified as part of DEC analysis. This article focuses on the first objective that is WENRA RL T4.2. Estimating a 10−4 Return Level for natural hazards is generally based on the application of the statistical Extreme Value Theory (EVT). In case of lack of reliable data or intermittent phenomenon, it is difficult to estimate such a level. With regard to the intensity of natural hazard to be used to define the protections, EDF has developed an approach distinguishing 3 types of hazards: - Those for which 10−4 level is definable, as earthquake, external flooding and tornado. For these hazards, the facilities are already protected against this level of hazard. - Those for which the 10−4 level is evaluated indirectly, such as cold temperatures, warm temperatures, and high winds. For those, EDF defined a “WENRA hazard”, which complements the Design Basis Hazard, and verified the capacity of the facilities to cope with it. This hazard is determined on the basis of a value with a “reasonably quantifiable” frequency of occurrence (typically a 100-year return period), to which EDF then adds a margin to target a level of risk that can reach a 10−4 level. The method of quantification of this margin crosses different approaches (mainly the gap between the observed records and statistical extrapolation) - Those for which the 10−4 level is considered not relevant, such as lightning or snow. For lightning, the robustness is ensured on the one hand by taking into account for the Design Basis lightning the highest level of the standard AFNOR NF EN 62305-1 and on the other hand by the protection of the hardened safety core equipments against an extreme lightning level. For snow, protection is based on the normative context with margins for some sites. The robustness of the structures and the organizational arrangements make it possible to cope with snow levels higher than those used for the design basis. In conclusion, the capacity of the EDF 900 MW NPPs to cope with high level of natural hazard (equivalent to decamillennial events) is being verified through the 4th periodic safety reviews, in compliance with WENRA reference level T4.2.

Results of Analysis of Aging Related Events at Ukrainian NPPs

The design lifetime (30 years) of Ukrainian NPPs has already been expired or will be expired soon. One of the priority areas for the development of nuclear energy is long-term operation (LTO) based on the results of periodic safety review. At present, eleven Ukrainian NPP units are operated under LTO conditions, which in turn causes certain features of operation related to wear, fatigue and general aging of components and structures. An issue of aging management is considered one of the main factors to ensure the safety of a nuclear installation, both in the design lifetime and in the long-term operation. The primary purpose of aging management is to ensure the safety and maximum efficiency of operation through the implementation of technically and economically feasible measures aimed at timely detection and keeping of degradation of NPP components caused by aging within the limits. One way to determine the efficiency of implemented measures and aging management programs is to analyze operational experience and, in particular, analyze the number of NPP operational occurrences during the design and long-term operation period and that are directly related to the aging effects. This paper presents the results of the analysis of the events at Ukrainian NPPs caused by aging processes, compares the results of national and international experience.

Experience Obtained and Lessons Learnt from the Transition of Ukrainian NPPs to Long-Term Operation

Nuclear energy is a strategic Ukrainian industry that produces more than 50% of electricity at present. Over the last decade during the operation of Ukrainian NPPs, the set of technical matters have been found and corresponding tasks shall be decided with engaging of scientific potential of the country. One of such matter is a safety justification of NPP components and structures for the period that is bigger than an initial design one and that is defined as transition from design operation to the long-term operation (LTO). From the end of 2010 to the beginning of 2020, the State Nuclear Regulatory Inspectorate of Ukraine granted 11 licenses for 11 power units based on positive results of the state assessment and review of Periodic Safety Review Reports considering mandatory safety review each ten years. These results became possible due to the coordinated, conscientious and longstanding work of thousands of highly qualified nuclear experts, which led to the fact that Ukraine now has a unique experience in preparation for a transition of various types of WWER-1000 and WWER-440 reactors to LTO. The summarized results and lessons learnt from the practice of transition to LTO are presented in this paper.