Relevant Quality Attributes Research Articles

Validación de la conservación de la cadena de frío durante la distribución de mezclas de nutrición parenteral

ObjectiveThis study aims to demonstrate the suitability of the process used to condition the extemporaneous mixtures of parenteral nutrition for distribution, considering the objective of preserving the cold chain during transport until it reaches the patient, necessary to ensure stability, effectiveness and safety of these mixtures. MethodConcurrent validation, design and implementation of a protocol for evaluating the process of packaging and distribution of MNPE developed by a pharmaceutical laboratory. Running tests, according to predefined acceptance criteria. It is performed twice, in summer and on routes that require longer transfer time. Evaluation of conservation of temperature by monitoring the internal temperature values of each type of packaging, recorded by data loggers calibrated equipment. ResultsThe different tests meet the established criteria. The collected data ensure the maintenance of the cold chain for longer than the transfer time to the most distant points. ConclusionsThis study establishes the suitability of the processes to maintaining the cold chain for transfer from the laboratory to the patient pharmacist. Whereas the breaking of cold chain can cause changes of compatibility and stability of parenteral nutrition and failures nutritional support, this study contributes to patient safety, one of the relevant dimensions of quality of care the health.

Next-generation cell line selection methodology leveraging data lakes, natural language generation and advanced data analytics.

Cell line development is an essential stage in biopharmaceutical development that often lies on the critical path. Failure to fully characterise the lead clone during initial screening can lead to lengthy project delays during scale-up, which can potentially compromise commercial manufacturing success. In this study, we propose a novel cell line development methodology, referenced as CLD 4, which involves four steps enabling autonomous data-driven selection of the lead clone. The first step involves the digitalisation of the process and storage of all available information within a structured data lake. The second step calculates a new metric referenced as the cell line manufacturability index (MI CL) quantifying the performance of each clone by considering the selection criteria relevant to productivity, growth and product quality. The third step implements machine learning (ML) to identify any potential risks associated with process operation and relevant critical quality attributes (CQAs). The final step of CLD 4 takes into account the available metadata and summaries all relevant statistics generated in steps 1-3 in an automated report utilising a natural language generation (NLG) algorithm. The CLD 4 methodology was implemented to select the lead clone of a recombinant Chinese hamster ovary (CHO) cell line producing high levels of an antibody-peptide fusion with a known product quality issue related to end-point trisulfide bond (TSB) concentration. CLD 4 identified sub-optimal process conditions leading to increased levels of trisulfide bond that would not be identified through conventional cell line development methodologies. CLD 4 embodies the core principles of Industry 4.0 and demonstrates the benefits of increased digitalisation, data lake integration, predictive analytics and autonomous report generation to enable more informed decision making.

Purity and DNA content of AAV capsids assessed by analytical ultracentrifugation and orthogonal biophysical techniques

Development and manufacturing adeno-associated virus (AAV)-based vectors for gene therapy requires suitable analytical methods to assess the quality of the formulations during development, as well as the quality of different batches and the consistency of the processes. Here, we compare biophysical methods to characterize purity and DNA content of viral capsids from five different serotypes (AAV2, AAV5, AAV6, AAV8, and AAV9). For this purpose, we apply multiwavelength sedimentation velocity analytical ultracentrifugation (SV-AUC) to obtain the species' contents and to derive the wavelength-specific correction factors for the respective insert-size. In an orthogonal manner we perform anion exchange chromatography (AEX) and UV-spectroscopy and the three methods yield comparable results on empty/filled capsid contents with these correction factors. Whereas AEX and UV-spectroscopy can quantify empty and filled AAVs, only SV-AUC could identify the low amounts of partially filled capsids present in the samples used in this study. Finally, we employ negative-staining transmission electron microscopy and mass photometry to support the empty/filled ratios with methods that classify individual capsids. The obtained ratios are consistent throughout the orthogonal approaches as long as no other impurities and aggregates are present. Our results show that the combination of selected orthogonal methods can deliver consistent empty/filled contents on non-standard genome sizes, as well as information on other relevant critical quality attributes, such as AAV capsid concentration, genome concentration, insert size length and sample purity to characterize and compare AAV preparations.

Proposed Design of Service Quality Performance Management System for Indonesian HSR

In some countries, the development of High-Speed Railway (HSR) represents a significant technological advancement which helps modern society’s value of time and various activities. Despite of having complex operational support and significant financial outlays, studies have shown that HSR sector has several growth barriers due to poor punctuality, reliability, pricing, and inconvenient passenger journeys. These brought specific impact on deciding factors whether or not passengers choose the transport option as it affected passenger satisfaction level. Recognizing the global challenge, this paper anticipates the impending Indonesian HSR operation by observing passengers’ relevant service quality attributes. The findings served as the performance management design’s foundation. In order to assist HSR operators to improve passenger experience and satisfaction, this study aims to identify the relevant service quality of Indonesian HSR potential passengers as one of many solutions to eliminate lack of demand problem. Qualitative and quantitative data analysis from in-depth interviews with several Indonesian railway expert and information from prior publication of Asian HSR which was used to carry out external benchmarking, validate results, support design process, and create contextual performance indicators for attributes using Knowledge-Based Performance Management System (KBPMS). This paper produced numbers of service quality performance indicators whose prioritization was arranged in specific order. Five variables are used to measure tangibility attributes’ performance, whereas six variables are used to measure reliability attributes’ performance. Tangibility and reliability were chosen based on Indonesian railway market preference and common success factor of HSR best practices. This performance indicators were specifically developed based on these attributes’ sub-attributes which has been contextualized. In contrast to other countries, Indonesian HSR place a distinctive value on physical facilities as it affects travelling motivation. These new insights would direct Indonesian HSR operators to develop targeted solutions to increase passenger satisfaction and economic benefits.

A Data Driven Approach to Support Tailored Clinical Programs for Biosimilar Monoclonal Antibodies.

Biosimilar monoclonal antibodies (mAbs) have been approved in the European Union since 2013 and have been demonstrated to reduce healthcare costs and to expand patient access. Biosimilarity is mainly established on the basis of demonstrated similarity of relevant quality attributes (QAs), determined by comprehensive physiochemical and functional analyses, and demonstration of bioequivalence. In addition, comparative efficacy/safety studies have been requested for all approved biosimilar mAbs so far, although the European Medicines Agency (EMA) Guidelines state that such confirmatory clinical trials may not be necessary in specific circumstances. In order to evaluate the degree of analytical similarity, how residual uncertainty regarding biosimilarity was resolved, and the value of clinical data, we analyzed the quality and clinical data packages for authorized adalimumab (7 products) and bevacizumab (5 products) biosimilars. The percentage of biosimilar batches meeting the similarity range for QAs, as defined by the biosimilar manufacturer based on a comprehensive characterization of the EU reference product (RP), was determined and clinical data were reviewed. Our analyses show that QAs of approved adalimumab and bevacizumab biosimilars have varying concordance with the EU-RP similarity range. In this study, we found that clinical efficacy data played a limited role in addressing quality concerns. Therefore, we encourage a regulatory review of the standards for clinical data requirements for mAb and fusion protein biosimilars. This study outlines a quality data driven approach for facilitating tailored clinical programs for biosimilars.

External Quality Assurance programs for processing methods provide evidence on impact of preanalytical variables

An annual External Quality Assurance (EQA) program has been provided to processing laboratories over the last ten years, allowing them to assess the performance of their processing methods, such as nucleic acid extractions or peripheral blood mononuclear cell (PBMC) isolation and cryopreservation. The objective of this study was to perform a global analysis on almost 1000 EQA scheme/participant data in order to assess (i) the impact of critical preanalytical factors on quantitative or qualitative attributes of different types of specimens and (ii) laboratory performance pattern over time. Statistical analysis was performed within each EQA scheme based on categorized preanalytical data provided by the participants and on centralized measurements of relevant quality attributes of the produced specimens (z-scores): DNA, cell-free (cf)DNA or RNA extraction from blood, DNA or RNA extraction from formalin fixed tissue, DNA or RNA extraction from frozen tissue, DNA extraction from saliva or stool, viable PBMC isolation and cryopreservation. The most critical preanalytical factors in nucleic acid extraction schemes were the nucleic acid extraction method and kit, the elution buffer, the enzymes used during extraction, the input material quantity and the storage temperature. Several indications of laboratory performance improvement over time could be seen. The conclusions are that EQA for processing methods provides unique evidence-based insights into the impact of preanalytical factors and the comparative performance of different processing methods and kits, while supporting laboratories in validating their processing methods.

Dry powder inhalation technology for heart targeting applied to calcium phosphate nanoparticles loaded with active substances

A dry powder for inhalation, composed of mannitol microparticles carrying calcium phosphate nanoparticles, has been developed for cardiac delivery of loaded bioactive peptide. The goal was to achieve highly efficient deposition of microparticles in the deep lung for release and translocation of drug loaded nanoparticles into blood, enabling a direct transport to the heart via the pulmonary vein. In this work, the relevant quality attributes of inhalable microparticles embedding nanoparticles were discussed. Furthermore, peptide drug release from microparticles was studied in vitro and correlated to microparticle dissolution and nanoparticle degradation.

Quality Assessment of Digital Health Applications: Protocol for a Scoping Review.

BackgroundAll over the world, development and usage of mobile health (mHealth) apps is increasing. While apps offer numerous opportunities to improve health care, there are associated problems that differ significantly from those of traditional health care services. Further investigations on the quality of mHealth apps are needed to address these problems.ObjectiveThis study aims to identify and map research on quality assessment and quality assurance of mHealth apps and their transferability to continuous quality assurance of mHealth apps.MethodsThe scoping review will follow published methodological frameworks for scoping studies as well as Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews criteria. Electronic databases (Medline, EMBASE, and PsycINFO), reference lists of relevant articles, and websites of relevant institutions will be searched. Two reviewers will independently assess eligibility of articles. Therefore, a 2-stage (title and abstract, followed by full text) screening process was conducted. Quality management systems and quality assessment tools will be analyzed and included in our review. Particular focus is placed on quality dimensions.ResultsThis scoping review provides an overview of the available evidence and identifies research gaps regarding continuous quality assessment of mHealth apps. Thereby, relevant quality dimensions and criteria can be identified and their eligibility and relevance for the development of a continuous quality assurance system of mHealth apps can be determined. Our results are planned to be submitted to an indexed, peer-reviewed journal in the second half of 2022.ConclusionsThis is the first review in the context of continuous quality assurance of mHealth apps. Our results will be used within the research “Continuous quality assurance of Digital Health Applications” (“QuaSiApps”) project funded by the German Federal Joint Committee.International Registered Report Identifier (IRRID)DERR1-10.2196/36974

Establishing Analytical and Functional Comparability for Biosimilars

A biosimilar is a drug product that has been deemed to be highly similar to its off-patent reference product in terms of purity, molecular structure, and bioactivity. Approvals to such products are granted on the basis of unambiguous demonstration of “no clinically meaningful differences” between the reference and the intended biosimilar. For a successful biosimilar approval, establishing analytical and functional biosimilarity across all relevant critical quality attributes is an essential prerequisite. This critical activity is performed using a combination of orthogonal, high-resolution tools that can accurately quantitate the minor differences that exist. In this article, we review key findings from some of the recent biosimilarity assessments that we have published on biosimilars of granulocyte-colony-stimulating factor (G-CSF), insulin glargine, rituximab, and trastuzumab.

Interlaboratory Studies Using the NISTmAb to Advance Biopharmaceutical Structural Analytics.

Biopharmaceuticals such as monoclonal antibodies are required to be rigorously characterized using a wide range of analytical methods. Various material properties must be characterized and well controlled to assure that clinically relevant features and critical quality attributes are maintained. A thorough understanding of analytical method performance metrics, particularly emerging methods designed to address measurement gaps, is required to assure methods are appropriate for their intended use in assuring drug safety, stability, and functional activity. To this end, a series of interlaboratory studies have been conducted using NISTmAb, a biopharmaceutical-representative and publicly available monoclonal antibody test material, to report on state-of-the-art method performance, harmonize best practices, and inform on potential gaps in the analytical measurement infrastructure. Reported here is a summary of the study designs, results, and future perspectives revealed from these interlaboratory studies which focused on primary structure, post-translational modifications, and higher order structure measurements currently employed during biopharmaceutical development.

Multi attribute method implementation using a High Resolution Mass Spectrometry platform: From sample preparation to batch analysis.

Quality control of biopharmaceuticals such as monoclonal antibodies (mAbs) has been evolving and becoming more challenging as the requirements of the regulatory agencies increase due to the demanding complexity of products under evaluation. Mass Spectrometry (MS)-based methods such as the multi-attribute method (MAM) are being explored to achieve a deeper understanding of the attributes critical for the safety, efficacy, and quality of these products. MAM uses high mass accuracy/high-resolution MS data that enables the direct and simultaneous monitoring of relevant product quality attributes (PQAs, in particular, chemical modifications) in a single workflow, replacing several orthogonal methods, reducing time and costs associated with these assays. Here we describe a MAM implementation process using a QTOF high resolution platform. Method implementation was accomplished using NIST (National Institute for Standards and Technology) mAb reference material and an in-process mAb sample. PQAs as glycosylation profiles, methionine oxidation, tryptophan dioxidation, asparagine deamidation, pyro-Glu at N-terminal and glycation were monitored. Focusing on applications that require batch analysis and high-throughput, sample preparation and LC-MS parameters troubleshooting are discussed. This MAM workflow was successfully explored as reference analytical tool for comprehensive characterization of a downstream processing (DSP) polishing platform and for a comparability study following technology transfer between different laboratories.

ESQuMo

Embedded systems are increasingly used in our daily life due to their importance. They are computer platforms consisting of hardware and software. They run specific tasks to realize functional and non functional requirements. Several specific quality attributes were identified as relevant to the embedded system domain. However, the existent general quality models do not address clearly these specific quality attributes. Hence, the proposition of quality models which address the relevant quality attributes of embedded systems needs more attention and investigation. The major goal of this paper is to propose a new quality model (called ESQuMo for Embedded Software Quality Model) which provides a better understanding of quality in the context of embedded software. Besides, it focuses the light on the relevant attributes of the embedded software and addresses clearly the importance of these attributes. In fact, ESQuMo is based on the well-established ISO/IEC 25010 standard quality model.

Establishing the Bioequivalence Safe Space for Immediate-Release Oral Dosage Forms using Physiologically Based Biopharmaceutics Modeling (PBBM): Case Studies

For oral drug products, in vitro dissolution is the most used surrogate of in vivo dissolution and absorption. In the context of drug product quality, safe space is defined as the boundaries of in vitro dissolution, and relevant quality attributes, within which drug product variants are expected to be bioequivalent to each other. It would be highly desirable if the safe space could be established via a direct link between available in vitro data and in vivo pharmacokinetics. In response to the challenges with establishing in vitro-in vivo correlations (IVIVC) with traditional modeling approaches, physiologically based biopharmaceutics modeling (PBBM) has been gaining increased attention. In this manuscript we report five case studies on using PBBM to establish a safe space for BCS Class 2 and 4 across different companies, including applications in an industrial setting for both internal decision making or regulatory applications. The case studies provide an opportunity to reflect on practical vs. ideal datasets for safe space development, the methodologies for incorporating dissolution data in the model and the criteria used for model validation and application. PBBM and safe space, still represent an evolving field and more examples are needed to drive development of best practices.

Scout-bot: Leveraging API Community Knowledge for Exploration and Discovery of API Learning Resources


 
 
 Application Programming Interface (API) is a core technology that facilitates developers’ productivity by enabling the reuse of software components. Understanding APIs and gaining knowledge about their usage are therefore fundamental needs for developers. Here, API documentation plays a pivotal role in enabling developers to take full advantage of the benefits brought by APIs. The quality of API documentation has therefore become an important concern given the celerity and dynamics at which APIs are now being made available to users. This article aims at exploring existing research in the area of API documentation in order to identify the associated quality dimensions addressed by the literature. The research is carried out as a systematic mapping study where 103 research papers selected from the literature were reviewed and a total of 5 core quality dimensions were identified and analyzed. By focusing on the two most relevant quality dimensions (understandability and completeness), this article presents an approach to enable API users to explore, discover and learn about APIs through API topic issues discussed in Stack Overflow (SO). We demonstrate the feasibility of our approach through Scout-bot, our tool for exploration and discovery of API topic issues.
 
 

An Incremental Model Projection Applied to Streamline Software Architecture Assessment and Monitoring

Managing software architecture represents a big challenge throughout the development lifecycle. The complexity of the involved structural elements and the relations among them make the specified models look oversized and fuzzy, which makes the architecture incomprehensible, hard to maintain, and difficult to assess its quality. This paper's goal is to propose a powerful methodology for simplifying and reducing models' complexity to increase understandability, smoothing maintenance, and facilitating architecture monitoring and assessment. For this purpose, the authors rely heavily on two major concepts, multi-view modeling, and incremental model projection. The multi-viewing requires that all models must have two main views to describe the architecture and the mapping to its relevant quality attributes. The incremental projection is a methodology used to specialize and minimize models progressively to make them simpler and clearer. The results show that projecting models incrementally can reduce and narrow them significantly.

Changes of carotenoid content in carrots after application of pulsed electric field treatments

Under certain conditions, pulsed electric fields (PEF) can promote the accumulation of phytochemicals through a stress-mediated response in plant tissues. Likewise, electropermeabilization of cell membranes can also improve the extraction of intracellular compounds. The objective of this study was to evaluate the main causes driving the increase in carotenoids content in PEF-treated carrots and to study the impact of those treatments on their relevant quality attributes. Carrots were treated with PEF differing in electric field strength (E) (0.8, 2 and 3.5 kV/cm) and number of pulses (5, 12 and 30). Individual carotenoids content, colour, pH and total soluble solids (TSS) were determined after 0 h and 24 h after PEF treatment. Total and individual carotenoid contents (phytoene and β-carotene) increased just after applying E ≥ 2 kV/cm, whereas lutein concentration decreased, and that of α-carotene remained similar to that found in untreated carrots. After applying 2 and 3.5 kV/cm, TSS and pH remained unaltered, but cortical browning index increased, which was correlated to carotenoid content. Increase in total carotenoid content is likely related to better extractability, but differences in the content of individual compounds suggest that PEF may also act by modulating their biosynthesis or causing their degradation.

Fuzzy Theory Based Quality Assessment of Multivariate Electrical Measurements of Smart Grids

Electrical measurements of smart grids form the backbone of various data driven applications. Proper analysis of these measurements can result in improved system planning, operation, monitoring and protection. However, the efficacy of smart grid data mining is highly influenced by the quality of the data. Hence, quality assessment of smart grid data is essential prior to the usage of the data in various applications. A fuzzy assessment method is proposed in this paper for assessing quality of multivariate electrical measurements of smart grids. At first, relevant quality dimensions of smart grid data are identified. Then, based on certain desirable characteristics, novel membership functions are proposed for assessing the data quality with respect to each of the considered dimensions. The proposed membership functions are evaluated on the current and real power measurements obtained from the power flow analysis of the IEEE 14-bus system. In addition, the proposed method is also implemented on the voltage, current and the real power measurements obtained from the power flow analysis of an actual 34 node feeder located in Arizona. The impact of measurement noise is also investigated by polluting the original measurements with Gaussian noise. It is found that the quality of the noisy measurements worsens with the increase in variance of the added noise. The proposed method has also been validated on a database containing practical SCADA and PMU measurements of the Southern Regional Grid of India. It is found that the PMU datasets are relatively incomplete compared to the SCADA datasets. In addition, the obtained results indicate that PMU data are suitable for use in more number of applications compared to the SCADA datasets. Unlike the existing methods, the proposed method can be used for quantifying the quality of any smart grid dataset that contains electrical measurements of multiple power system variables including boolean variables such as circuit breaker status. Moreover, unlike the existing methods, the proposed method can measure the consistency among the measurements. In addition, the proposed method is found to be sensitive to the distribution of the bad measurements in a given database.

Comparison of consistency and complementarity of reporting biosimilar quality attributes between regulatory and scientific communities: An adalimumab case study

Biosimilar approval relies on the comparability of quality attributes (QAs), for which information can be derived from regulatory or scientific communities. Limited information is known about whether these sources are consistent with or complementary to each other. The consistency and complementarity of QA reporting in biosimilarity assessments for adalimumab biosimilars approved by the European Medicines Agency in European public assessment reports (EPARs) and scientific publications was assessed. A classification of 77 different QAs (53 structural and 24 functional attributes) was used to assess the types of and information on QAs reported. Six adalimumab biosimilars were analyzed, for which the number of QAs reported in EPARs and publications varied (range = 47 [61%]–60 [78%]). The proportion of QAs consistently reported in both sources varied (range = 28%–75%) among biosimilars; functional QAs (mean = 21 QAs [88%]; range = 19–23) were more consistently reported than structural QAs (mean = 33 QAs [62%]; range = 27–34). The EPARs frequently reported biosimilarity interpretation without providing test results (9–57 QAs in EPARs versus 0–8 QAs in publications), whereas publications frequently reported both test results and interpretations (13–40 QAs in publications versus 0–3 QAs in EPARs). Both sources provided information on the biosimilarity of QAs in a complementary manner and the same biosimilarity interpretation of test results for reported QAs (mean = 90%; range = 78%–100%), with a small discrepancy in biosimilarity interpretations of a few clinically relevant QAs related to post-translation modifications and biological activity. Comprehensive reporting of QAs can contribute to an improved understanding of the role of structural and functional attributes in establishing biosimilarity and the mechanism of action of biological substances in general.

Quality of urban green spaces influences residents' use of these spaces, physical activity, and overweight/obesity.

The quality characteristics of urban green spaces (UGS) have been suggested to play a critical role in their use and their potentials to exert health effects. However, epidemiological studies evaluating such a role are scarce. These studies have generally focused on a limited number of quality dimensions. We studied the association between 10 UGS quality dimensions, assessed through a comprehensive multidimensional tool, and physical activity, overweight/obesity, and UGS use. Our study was based on 2053 adults participating in the Barcelona Health Survey (2016) and the quality of 149 UGS located in Barcelona, Spain. For each participant, we abstracted the average and maximum quality score separately for each of the 10 quality dimensions and an overall quality score for the UGS within 300m of the participant's residential address. Data on the study outcomes were obtained through face-to-face interviews. We developed logistic regression and negative binomial models to assess our evaluated associations and conducted mediation analyses between the different outcomes. We observed that the overall quality of UGS was associated with higher likelihood of engaging in moderate-to-vigorous physical activity (OR:1.13; 95% CI:1.00-1.27), lower risk of overweight/obesity (OR: 0.88; 95% CI: 0.79-0.98), and increased use of UGS (exponentiated regression coefficient: 1.08; 95% CI:1.01-1.15). For the quality dimensions, we observed different patterns of associations depending on the outcome; however, bird biodiversity and amenities seem to be relevant to all of our evaluated outcomes. The mediation analysis suggested that UGS use mediate the association between quality and physical activity, while physical activity mediates the association between quality and overweight/obesity. The novel results from this study will allow decision-makers better design UGS and directly pinpoint relevant quality dimensions to promote physical activity, reduce the risk of overweight/obesity and boost the use of UGS amongst citizens.

Effects of Starch Incorporation on the Physicochemical Properties and Release Kinetics of Alginate-Based 3D Hydrogel Patches for Topical Delivery.

The development of printable hydrogel inks for extrusion-based 3D printing is opening new possibilities to the production of new and/or improved pharmaceutical forms, specifically for topical application. Alginate and starch are natural polysaccharides that have been extensively exploited due to their biocompatibility, biodegradability, viscosity properties, low toxicity, and relatively low cost. This research work aimed to study the physicochemical and release kinetic effects of starch incorporation in alginate-based 3D hydrogel patches for topical delivery using a quality by design approach. The incorporation of a pregelatinized starch is also proposed as a way to improve the properties of the drug delivery system while maintaining the desired quality characteristics. Critical material attributes and process parameters were identified, and the sensitivity and adequacy of each parameter were statistically analyzed. The impact of alginate, starch, and CaCl2·2H2O amounts on relevant quality attributes was estimated crosswise. The amount of starch revealed a synergetic impact on porosity (p = 0.0021). An evident increase in the size and quantity of open pores were detected in the as printed patches as well as after crosslinking (15.6 ± 5.2 µm). In vitro drug release studies from the optimized alginate-starch 3D hydrogel patch, using the probe Rhodamine B, showed an initial high burst release, followed by a controlled release mechanism. The results obtained also showed that the viscoelastic properties, printing accuracy, gelation time, microstructure, and release rates can be modulated by varying the amount of starch added to the system. Furthermore, these results can be considered an excellent baseline for future drug release modulation strategies.