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IntroductionThe European Medicines Agency (EMA) offers scientific advice to support the qualification procedure of novel methodologies, such as preclinical and in vitro models, biomarkers, and pharmacometric methods, thereby endorsing their acceptability in medicine research and development (R&D). This aspect is particularly relevant to overcome the scarcity of data and the lack of validated endpoints and biomarkers in research fields characterized by small samples, such as pediatrics.AimThis study aimed to analyze the potential pediatric interest in methodologies qualified as “novel methodologies for medicine development” by the EMA.MethodsThe positive qualification opinions of novel methodologies for medicine development published on the EMA website between 2008 and 2023 were identified. Multi-level analyses were conducted to investigate data with a hierarchical structure and the effects of cluster-level variables and cluster-level variances and to evaluate their potential pediatric interest, defined as the possibility of using the novel methodology in pediatric R&D and the availability of pediatric data. The duration of the procedure, the type of methodology, the specific disease or disease area addressed, the type of applicant, and the availability of pediatric data at the time of the opinion release were also investigated.ResultsMost of the 27 qualifications for novel methodologies issued by the EMA (70%) were potentially of interest to pediatric patients, but only six of them reported pediatric data. The overall duration of qualification procedures with pediatric interest was longer than that of procedures without any pediatric interest (median time: 7 months vs. 3.5 months, respectively; p = 0.082). In parallel, qualification procedures that included pediatric data lasted for a longer period (median time: 8 months vs. 6 months, respectively; p = 0.150). Nephrology and neurology represented the main disease areas (21% and 16%, respectively), while endpoints, biomarkers, and registries represented the main types of innovative methodologies (32%, 26%, and 16%, respectively).DiscussionOur results underscore the importance of implementing innovative methodologies in regulatory-compliant pediatric research activities. Pediatric-dedicated research infrastructures providing regulatory support and strategic advice during research activities could be crucial to the design of ad hoc pediatric methodologies or to extend and validate them for pediatrics.

On-site partial discharge (PD) measurements have turned out to be a very efficient technique for determining the insulation condition in high-voltage electrical grids (AIS, cable systems, GIS, HVDC converters, etc.); however, there is not any standardised procedure for determining the performances of PD measuring systems. In on-line and on-site PD measurements, high-frequency current transformers (HFCTs) are commonly used as sensors as they allow for monitoring over long distances in high-voltage installations. To ensure the required performances, a metrological qualification of the PD analysers by applying an evaluation procedure is necessary. A novel evaluation procedure was established to specify the quantities to be measured (electrical charge and PD repetition rate) and to describe the evaluation tests considering the measured influence parameters: noise, charge amplitude, pulse width and time interval between consecutive pulses. This procedure was applied to different types of PD analysers used for off-line measurements, sporadic on-line measurements and continuous PD monitoring. The procedure was validated in a round-robin test involving two metrological institutes (RISE from Sweden and FFII from Spain) and three universities (TUDelft from the Netherlands, TAU from Finland and UPM from Spain). With this round-robin test, the effectiveness of the proposed qualification procedure for discriminating between efficient and inappropriate PD analysers was demonstrated. Furthermore, it was shown that the PD charge quantity can be properly determined for on-line measurements and continuous monitoring by integrating the pulse signals acquired with HFCT sensors. In this case, these sensors must have a flat frequency spectrum in the range between several tens of kHz and at least two tens of MHz, where the frequency pulse content is more significant. The proposed qualification procedure can be useful for improving the future versions of the technical specification TS IEC 62478 and the standard IEC 60270. [ABSTRACT FROM AUTHOR]

The insulation condition of HVDC grids consisting of cable systems, GIS, and converters should be monitored by partial discharge (PD) analysers using artificial intelligence (AI) tools for efficient insulation diagnosis. Although there are many experiences of PD monitoring solutions developed for the supervision of the insulation condition of HVAC grids using PD analysers, there are no standardised requirements for their qualification available yet. The international technical specification TS IEC 62478 provides general rules for PD measurements using electromagnetic methods but does not define performance requirements for qualification tests. HVDC and HVAC PD analysers must be tested by unambiguous test procedures. This paper compiles experiences of using PD analysers with HFCT sensors in HVAC grids (cable systems, GIS, and AIS) to define a qualification procedure for HVAC systems. This procedure is applicable to HVDC grids (cable systems, GIS, AIS, and converters) because the particularities related to the insulation behaviour under HVDC voltage are also considered. Representative PD sources are discussed in HVAC and HVDC positive and negative polarity. The PD pulse trend of representative insulation defects in HVDC cable systems is quite different from that of HVAC grids. Special attention should be paid to the acquisition of PD signals in HVDC grids since few pulses appear in solid insulations, mainly during voltage changes (polarity reversals or surges), but rarely in continuous operation with constant direct voltage. A synthetic PD simulator has been developed to reproduce trains of PD pulses or noise signals, similar to those that can appear in the power network. A set of three functionality tests has been developed for qualification of the diagnostic capabilities of PD analysers working up to 30 MHz addressed to HVDC or HVAC grids: (1) PD recognition test, (2) PD clustering test, and (3) PD location test. This qualification procedure has been validated by means of a round-robin test performed by five research institutes (RISE, FFII, TUDelft, TAU, and UPM) using commercial and in-development AI PD recognition and clustering tools to demonstrate its robustness and applicability. Applying this qualification procedure, two PD methods for electrical detection and prevention of insulation defects have been approved, one for HVAC and the other for HVDC grids. [ABSTRACT FROM AUTHOR]

The insulation condition of HVDC grids consisting of cable systems, GIS, and converters should be monitored by partial discharge (PD) analysers using artificial intelligence (AI) tools for efficient insulation diagnosis. Although there are many experiences of PD monitoring solutions developed for the supervision of the insulation condition of HVAC grids using PD analysers, there are no standardised requirements for their qualification available yet. The international technical specification TS IEC 62478 provides general rules for PD measurements using electromagnetic methods but does not define performance requirements for qualification tests. HVDC and HVAC PD analysers must be tested by unambiguous test procedures. This paper compiles experiences of using PD analysers with HFCT sensors in HVAC grids (cable systems, GIS, and AIS) to define a qualification procedure for HVAC systems. This procedure is applicable to HVDC grids (cable systems, GIS, AIS, and converters) because the particularities related to the insulation behaviour under HVDC voltage are also considered. Representative PD sources are discussed in HVAC and HVDC positive and negative polarity. The PD pulse trend of representative insulation defects in HVDC cable systems is quite different from that of HVAC grids. Special attention should be paid to the acquisition of PD signals in HVDC grids since few pulses appear in solid insulations, mainly during voltage changes (polarity reversals or surges), but rarely in continuous operation with constant direct voltage. A synthetic PD simulator has been developed to reproduce trains of PD pulses or noise signals, similar to those that can appear in the power network. A set of three functionality tests has been developed for qualification of the diagnostic capabilities of PD analysers working up to 30 MHz addressed to HVDC or HVAC grids: (1) PD recognition test, (2) PD clustering test, and (3) PD location test. This qualification procedure has been validated by means of a round-robin test performed by five research institutes (RISE, FFII, TUDelft, TAU, and UPM) using commercial and in-development AI PD recognition and clustering tools to demonstrate its robustness and applicability. Applying this qualification procedure, two PD methods for electrical detection and prevention of insulation defects have been approved, one for HVAC and the other for HVDC grids.

On-site partial discharge (PD) measurements have turned out to be a very efficient technique for determining the insulation condition in high-voltage electrical grids (AIS, cable systems, GIS, HVDC converters, etc.); however, there is not any standardised procedure for determining the performances of PD measuring systems. In on-line and on-site PD measurements, high-frequency current transformers (HFCTs) are commonly used as sensors as they allow for monitoring over long distances in high-voltage installations. To ensure the required performances, a metrological qualification of the PD analysers by applying an evaluation procedure is necessary. A novel evaluation procedure was established to specify the quantities to be measured (electrical charge and PD repetition rate) and to describe the evaluation tests considering the measured influence parameters: noise, charge amplitude, pulse width and time interval between consecutive pulses. This procedure was applied to different types of PD analysers used for off-line measurements, sporadic on-line measurements and continuous PD monitoring. The procedure was validated in a round-robin test involving two metrological institutes (RISE from Sweden and FFII from Spain) and three universities (TUDelft from the Netherlands, TAU from Finland and UPM from Spain). With this round-robin test, the effectiveness of the proposed qualification procedure for discriminating between efficient and inappropriate PD analysers was demonstrated. Furthermore, it was shown that the PD charge quantity can be properly determined for on-line measurements and continuous monitoring by integrating the pulse signals acquired with HFCT sensors. In this case, these sensors must have a flat frequency spectrum in the range between several tens of kHz and at least two tens of MHz, where the frequency pulse content is more significant. The proposed qualification procedure can be useful for improving the future versions of the technical specification TS IEC 62478 and the standard IEC 60270.

Introduction: The European Medicines Agency (EMA) offers scientific advice to support the qualification procedure of novel methodologies, such as preclinical and in vitro models, biomarkers, and pharmacometric methods, thereby endorsing their acceptability in medicine research and development (R&D). This aspect is particularly relevant to overcome the scarcity of data and the lack of validated endpoints and biomarkers in research fields characterized by small samples, such as pediatrics., Aim: This study aimed to analyze the potential pediatric interest in methodologies qualified as "novel methodologies for medicine development" by the EMA., Methods: The positive qualification opinions of novel methodologies for medicine development published on the EMA website between 2008 and 2023 were identified. Multi-level analyses were conducted to investigate data with a hierarchical structure and the effects of cluster-level variables and cluster-level variances and to evaluate their potential pediatric interest, defined as the possibility of using the novel methodology in pediatric R&D and the availability of pediatric data. The duration of the procedure, the type of methodology, the specific disease or disease area addressed, the type of applicant, and the availability of pediatric data at the time of the opinion release were also investigated., Results: Most of the 27 qualifications for novel methodologies issued by the EMA (70%) were potentially of interest to pediatric patients, but only six of them reported pediatric data. The overall duration of qualification procedures with pediatric interest was longer than that of procedures without any pediatric interest (median time: 7 months vs. 3.5 months, respectively; p = 0.082). In parallel, qualification procedures that included pediatric data lasted for a longer period (median time: 8 months vs. 6 months, respectively; p = 0.150). Nephrology and neurology represented the main disease areas (21% and 16%, respectively), while endpoints, biomarkers, and registries represented the main types of innovative methodologies (32%, 26%, and 16%, respectively)., Discussion: Our results underscore the importance of implementing innovative methodologies in regulatory-compliant pediatric research activities. Pediatric-dedicated research infrastructures providing regulatory support and strategic advice during research activities could be crucial to the design of ad hoc pediatric methodologies or to extend and validate them for pediatrics., Competing Interests: AB, GR, ET, and DB were employed by Consorzio per Valutazioni Biologiche e Farmacologiche (CVBF). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Giannuzzi, Bertolani, Torretta, Reggiardo, Toich, Bonifazi and Ceci.)

Objectives:Orally disintegrating (mini)tablets (OD(M)Ts) are of interest in the field of pharmaceutics. Their orodispersible character is defined by the disintegration time, which is measured with a basket apparatus according to the European Pharmacopoeia. This method, however, lacks applicability for ODTs and especially ODMTs. New disintegration apparatuses have been described in literature, but a qualification to assess the applicability has not been described. A qualification procedure for two automated disintegration apparatuses, OD-mate and Hermes apparatus, is introduced. Methods:Aspects of the operational qualification as well as precision and accuracy regarding a performance qualification were evaluated for both apparatuses analog to the ICH guideline Q2. While the OQ study is performed separately for each apparatus, accuracy and precision were performed following the same protocol for both testers. Key findings:Small RSDs (16.9% OD-mate; 15.2% Hermes compared to 32.3% for the pharmacopeial method) were found despite very fast disintegration times (1.5 s for both apparatuses). By comparing these RSDs to practical examples, the authors propose threshold values for repeatability depending on the mean disintegration time. Obtained results from the qualification were used to assess the applicability of both apparatuses. [ABSTRACT FROM PUBLISHER]