Analytical Quality Research Articles

Development of quality control parameters for two Bhutanese medicinal plants (Aster flaccidus Bunge and Aster diplostephioides (DC.) Benth. ex C.B.Clarke) using traditional and modern pharmacognostical platforms

Bhutan's scholarly traditional medical system is called Bhutanese Sowa Rigpa medicine (BSM). It was integrated with the modern healthcare system in 1967. Over 200 medicinal plants are used to produce more than 100 poly-ingredient medicinal formulations. Although BSM is supported by well-documented principles, pharmacopoeias, diagnostic procedures, treatment regimens, and traditional quality assurance systems, modern quality control parameters have become essential to distinguish closely related species and prevent contamination from exogenous impurities. This study aims to establish reliable analytical methods and quality control parameters for Aster flaccidus Bunge and Aster diplostephioides (DC.) Benth. ex C.B. Clarke used as ingredients in the BMS poly-ingredient medicinal formulations. Furthermore, their reported phytochemicals and biological activities are also discussed in this study. Standard pharmacognostic techniques, including macroscopical and microscopical examinations of crude drugs, were employed to establish the quality control parameters for two Aster species. The physicochemical limits were determined as per the World Health Organization (WHO)-recommended guidelines and methods described in the Thai herbal pharmacopoeia. A high-performance thin-layer liquid chromatography (HPTLC) was used to develop a comparative chromatogram/phytochemical fingerprint for the crude extracts obtained from two Aster species. A literature review was conducted to record their isolated phytochemicals and biological activities. Two Aster species possess macro- and microscopic features such as colour, appearance, and shape. Physicochemical analysis of crude drugs from two Aster species including HPTLC fingerprinting of their methanol crude extracts also yielded adequate data to differentiate and confirm two Aster species before adding them to the BSM poly-ingredient medicinal formulations. From the literature review, only A. flaccidus was found to be studied for its phytochemical constituents, whereby 11 pure compounds were isolated from aerial parts and roots. The current study revealed distinct species-specific distinguishing features, including ecological adaptation, micromorphology, anatomy, physicochemical values, HPTLC chromatograms. These parameters can be used to authenticate the species identity and prevent adulterations, thereby improving the quality and safety of BSM formulations.

ICH Q14-inspired novel approach to establish an SFC-based purity method for carbamazepine.

The proposed ICH Q14 guideline "Analytical procedure development" describes science and risk-based approaches for development and maintenance of analytical procedures suitable for the assessment of the quality of drug substances and drug products. As a case study, the systematic development and validation of a supercritical fluid chromatography (SFC)-based purity method for carbamazepine is presented. Systematic analytical quality by design (AQbD) principles were applied using the software package Fusion QbD to the method development approach. The relationship between chromatographic parameters and the responses of interest were examined to improve the reliability of the method by understanding, reducing, and controlling sources of variability. Method performance qualification in terms of method robustness was finally carried out with the parameters that were classified as critical after method development and a validation study met previously set acceptance criteria. The developed SFC purity method for carbamazepine demonstrated readiness as a viable alternative to the official HPLC method published in the Ph.Eur. with improved peak resolution, improved peak symmetry, and faster analysis times (3min vs. 80 min for the official method). Its inherent reliability illustrates the superiority of AQbD in method development and application for drug quality assurance.

Analytical quality by design aided stability indicating a robust ultra‐performance liquid chromatographic technique for the quantification of sonidegib and its organic impurities in bulk drug substance

AbstractA simple quality by design aided stability indicating method was developed for quantification of sonidegib (SONI) and its process related impurities using on ultra‐performance liquid chromatography in bulk drug substance. AutoChrom and Design‐Expert software were used to predict physicochemical properties, draw Ionization graphs, and generate analytical target profile. SONI was subjected to forced degradation conditions, such as oxidative, acid hydrolysis, base hydrolysis, hydrolytic, thermal, and photolytic hydrolysis. All degradation products and process contaminants were separated using an Acquity Ethylene Bridged Hybrid C18 column in gradient elution mode with a mobile phase containing 0.02 M ammonium acetate buffer and acetonitrile: methanol (80:20 v/v). The predicted physicochemical properties are accurate and they facilitated for selection of robust conditions in development of chromatographic method with minimal trials. The developed method can be used for quantification of drug and its process related impurities in bulk drugs.

Quality assessment, HPTLC-DPPH, analytical quality by design based HPTLC method development for estimation of piperine in piper species and marketed formulations

BackgroundQuality assessment of herbs is an essential aspect. In this study HPTLC method is developed by employing the quality based optimization approach with the aid of analytical quality by design tools and the quality assessment of the Piper species. ResultThe Quality assessment was carried out for the piper species which was under the acceptance criteria of Ayurvedic Pharmacopeia of India. Eco-friendly and Quality based HPTLC method was developed and validated for Piperine in Extracts as well as marketed formulation. Further the antioxidant potential was checked by the HPTLC-DPPH (2,2-diphenyl-1-picrylhydrazyl) method. ConclusionQuality assessed extracts and Analytical quality based HPTLC method which was eco-friendly, simple and reliable was developed and validated.

Application of analytical quality by design (AQbD) for stability-indicating method development for quantification of nevirapine and its degradation products

Development of stability-indicating method by liquid chromatography are always a challenge for analytical researchers. A traditional way is by varying one chromatographic parameter at a time assessing the responses from each test. Recent international guidelines encourage the implementation of systematic approaches in analytical development, such as Analytical Quality by Design (AQbD). The aim of this paper was to develop, using the AQbD approach, an efficient and selective stability-indicating method by high performance liquid chromatography for nevirapine and its related substances. The Analytical Target Profile (ATP) and the Critical Method Attributes (CMA) were determined. Through the risk assessment studies, the high-risk analytical conditions were considered as Critical Method Parameters (CMP) and they were screened and optimized by Design of Experiment (DoE). The Method Operable Design Region (MODR) was defined using Monte Carlo Simulation. A control strategy was established by the definition of the system suitability of the analytical procedure. Optimal chromatographic conditions were achieved using an isocratic elution consisting of a mixture of 5 mM ammonium formate buffer pH 5.4/acetonitrile/methanol (60:20:20), with a flow rate of 1.0 mL/min, oven temperature of 30 °C, injection volume of 5 µL and an ACE C18 250 mm x 4,6 mm x 5 µm chromatographic column. Finally, analytical validation and forced degradation studies confirmed the performance of the analytical method. From the estimation of measurement uncertainty, strategies were outlined so that the method is fit for purpose throughout its life cycle. Additionally, guard bands were defined, changing the specification for nevirapine quantification from 90 % to 100 % to the acceptance zone of 92.1–107.9 %. The AQbD method development provided strong justifications for the selection of important parameters for nevirapine method during regulatory filling. Furthermore, with the pass/fail decision rule using guard band, restricted acceptance zones were defined, reducing the risk to the consumer of taking a drug product whose batch was inadequately approved.

Development of advanced PCR-based methods for accurate identification and authentication of commercial shrimp products

Shrimp is among the most economically valuable and susceptible seafood species to food fraud worldwide. The identities of 40 commercial shrimp products sold in South Korean markets were assessed using the standard barcoding method, revealing a significant 70% incidence of mislabeling. Based on these findings, three distinct PCR methods were developed to differentiate between eight predominant species (Penaeus vannamei, Pandalus borealis, Palaemon gravieri, Leptochela gracilis, Penaeus monodon, Pleoticus muelleri, Metapenaeopsis dalei, and Euphausia pacifica). Both conventional and real-time PCR (RT-PCR) showed specificity ranging from 0.0001 to 0.001 ng/μL, with no cross-reactivity against 18 reference species. These methods were further refined to create a multiplex ultrafast RT-PCR technique that could simultaneously identify seven shrimp species within 23 min while maintaining analytical accuracy that can be adapted for various analytical settings, field applications, rapid screening, quality control, and regulatory compliance, making them invaluable tools for the food industry and regulatory authorities.

Development and validation of simultaneous HPLC-PDA analysis method for quality control of Hwang-ryeon-hae-dok-tang: An analytical quality by design approach

This study introduces an advanced analytical method for quality control of botanical drugs, focusing on Hwang-ryeon-hae-dok-tang (HRHDT), a traditional herbal prescription utilized for inflammation, gastritis, fever, and hypertension. Botanical drugs pose a challenge due to their complex composition, requiring reliable and robust analytical techniques. Our step-by-step procedure included defining the analytical target profile, risk assessment, screening and optimizing design of experiment, measuring the design space, and Monte Carlo simulation. The established HPLC-PDA method enables the simultaneous analysis of four major compounds (geniposide, baicalin, palmatine, and berberine) present in HRHDT. The optimized conditions involve a gradient elution with acetonitrile and water, both containing 0.1% trifluoroacetic acid, a 32 °C column temperature, 254 nm detection wavelength, and 1.0 mL/min flow rate. A successful validation demonstrated excellent linearity (R2: 0.9984–0.9989) and accuracy (recovery: 100.61%–102.44%), with precise repeatability and intermediate precision (%RSD: 0.39%–0.83%). These results further confirm the reliability and accuracy of the analytical method. Overall, our design-based approach not only facilitated the development of robust analytical methods but also allowed for flexible operation ranges. Therefore, this methodology holds significant potential for ensuring the quality of botanical drug products within the pharmaceutical industry.

Stability Indicating RP-HPLC Method for the Estimation of Impurities in Esomeprazole Gastro-Resistant Tablets by AQbD Approach

Abstract Background: Esomeprazole (ESO) gastro-resistant tablets (40 mg) are sold under the brand name, Zosa, which effectively manages conditions associated with the overproduction of gastric acid, including peptic ulcer disease and Zollinger-Ellison syndrome. The present study quantifies impurities in esomeprazole using advanced analytical techniques known as analytical quality by design with high-performance liquid chromatography. Methods: Buffer selection (pH 7.6) and mobile phase composition (75:25 v/v) were optimized utilizing a YMC C18 column (150 mm × 4.6 mm; particle size, 3 μm) with a flow rate of 1.0 mL/min. The analyte was monitored with a UV/PDA detector at a wavelength of 280 nm. The stability-indicating nature of the method was confirmed based on forced degradation studies. The method validation was performed per ICH guidelines. Linearity, specificity, limit of detection, limit of quantification, precision, accuracy, solution stability, and robustness parameters were validated. Results: All validation parameters were within an acceptable range. Excellent linearity with correlation coefficient values > 0.99 was achieved across the quantification limit. The solution stability study demonstrated no significant increase in percent impurity over a 24-h period. Analytical quality by design was instrumental in defining the design range for buffer pH and mobile phase composition, ensuring robust method performance. It was confirmed that 75% buffer solution, 25% acetonitrile, and pH 7.6 were the ideal conditions for determination of ESO impurities. Conclusion: The validated method provides a reliable tool for accurately quantifying impurities in ESO tablet formulations.

Analytical quality by design approach to develop an eco-friendly RP-HPLC method for estimation of irbesartan in chitosan polymeric nanoparticles: forced degradation studies and assessment of in vitro release mathematical modelling.

Irbesartan is an angiotensin converting enzyme blocker, primarily utilized for the management of hypertension and the mitigation of diabetic nephropathy progression. The present study introduces rapid, robust and environmentally sustainable reverse phase high performance liquid chromatography (RP-HPLC) validated under the analytical quality by design (AQbD) framework according to ICH guidelines. Utilizing a central composite design, the method's systemic optimization was achieved, ensuring reproducibility and accuracy. Chromatographic separation was accomplished utilizing an ethanol and sodium acetate buffer (60 : 40 v/v) isocratic mobile phase system on a zorbax sb C18 column, with a flow rate of at 0.6 mL min-1. Studies on forced degradation outlined stability of irbesartan and its degradation processes, enhancing our understanding of its chemical robustness under varied conditions. Complementing the green chemistry paradigm, the method's environmental impact was critically assessed, affirming its alignment with sustainability objectives. The validated method proved pivotal in determining the percent entrapment and loading efficiency of the formulated nanoparticles and holds potential for application in biological matrices. Furthermore, the encapsulation of IRB within chitosan nanoparticles was explored to assess release kinetics and enhance bioavailability. This study not only advances the analytical sciences by merging eco-friendly practices with method development but also broadens the applicative landscape of HPLC methodologies in drug delivery research.

Artificial Intelligence and Blockchain Enabled Smart Healthcare System for Monitoring and Detection of COVID-19 in Biomedical Images.

Millions of individuals around the world have been impacted by the ongoing coronavirus outbreak, known as the COVID-19 pandemic. Blockchain, Artificial Intelligence (AI), and other cutting-edge digital and innovative technologies have all offered promising solutions in such situations. AI provides advanced and innovative techniques for classifying and detecting symptoms caused by the coronavirus. Additionally, Blockchain may be utilized in healthcare in a variety of ways thanks to its highly open, secure standards, which permit a significant drop in healthcare costs and opens up new ways for patients to access medical services. Likewise, these techniques and solutions facilitate medical experts in the early diagnosis of diseases and later in treatments and sustaining pharmaceutical manufacturing. Therefore, in this work, a smart blockchain and AI-enabled system is presented for the healthcare sector that helps to combat the coronavirus pandemic. To further incorporate Blockchain technology, a new deep learning-based architecture is designed to identify the virus in radiological images. As a result, the developed system may offer reliable data-gathering platforms and promising security solutions, guaranteeing the high quality of COVID-19 data analytics. We created a multi-layer sequential deep learning architecture using a benchmark data set. In order to make the suggested deep learning architecture for the analysis of radiological images more understandable and interpretable, we also implemented the Gradient-weighted Class Activation Mapping (Grad-CAM) based colour visualization approach to all of the tests. As a result, the architecture achieves a classification accuracy rate of 0.96, thus producing excellent results.

Analytical methods and experimental quality in studies targeting carbonyls in electronic cigarette aerosols.

We provide an extensive review of 14 studies (11 independent and three industry-funded) on emissions generated by Electronic Cigarettes (ECs), specifically focusing on the evaluation of carbonyls present in these emissions and emphasizing a meticulous evaluation of their analytical methods and experimental procedures. Since the presence of carbonyl by-products in EC aerosol is concerning, it is important to evaluate the reliability of emission studies quantifying these compounds by verifying their compliance with the following criteria of experimental quality: authors must 1) supply sufficient information on the devices and experimental procedures to allow for potentially reproducing or replicating the experiments, 2) use of appropriate puffing protocols that approach consumer usage as best as possible, 3) use of appropriate analytical methods and 4) usage of blank samples to avoid false positive detection. Outcomes were classified in terms of the fulfilment of these conditions as reliable in seven studies, partially reliable in five studies, and unreliable in two studies. However, only five studies used blank samples and six studies failed the reproducibility criterion. Carbonyl yields were far below their yields in tobacco smoke in all reproducible studies, even in the partially reliable ones, thus supporting the role of ECs (when properly tested and operated) as harm reduction products. This review highlights the necessity to evaluate the quality of laboratory standards in testing EC emissions to achieve an objective assessment of the risk profile of ECs.

Analytical hierarchy process-based maintenance quality function deployment integrating total quality management with total productive maintenance and its application in dairy industry

Analytical hierarchy process-based maintenance quality function deployment integrating total quality management with total productive maintenance and its application in dairy industry

Valuation of big data analytics quality and competitive advantage with strategic alignment model: from Greek philosophy to contemporary conceptualization

<abstract> <p>Around 333BC, Diogenes Laertius cited (Greek quote): "οὐκ ἐν τῷ μεγάλῳ τὸ εὖ…, ἀλλ᾿ ἐν τῷ εὖ τὸ μέγα", which means that volume (big data: tera, peta, velocity and variety) doesn't guarantee quality. Furthermore, Protagoras's doctrine about homo mensura and the Socratic Maieutic method evidences demonstrated the way that queries (SQL) on big data can play on specific needs when crafted, such as turning big data into knowledge and a competitive advantage. In this research, an alternative to the data-driven approach will be propounded with the development of the strategic alignment model (SAM) based on the principles of Greek philosophy. The SAM model will support decisions of big data analytics structure with strategies to fit and align in a way to create a competitive advantage. Mathematical formulation of the model will help to optimize a competitive advantage through the economic value added (EVA) to guide the proper strategy and big data analytics structure in a holistic framework. Conclusions will be drawn on how strategy and the structure of big data analytics can be aligned.</p> </abstract>

Analytical validation and diagnostic performance of the ASCL1/ZNF582 methylation test for detection of high-grade anal intraepithelial neoplasia and anal cancer

DNA methylation testing on biopsies can detect high-grade anal intraepithelial neoplasia (HGAIN) in need of treatment and anal cancer. This study aimed to analytically validate and determine the diagnostic performance of a newly developed multiplex quantitative methylation-specific PCR, PreCursor-M AnoGYN (RUO), combining ASCL1, ZNF582 and a reference (ACTB) in one assay. Analytical validation was performed on two qPCR devices using predefined quality criteria. Diagnostic performance was determined on a cross-sectional series of 111 anal biopsies covering all stages of anal disease. Differences in methylation levels were assessed using the Kruskal-Wallis test. Area under the curve was determined using logistic regression analysis. Detection rates were calculated at predefined specificities for the cross-sectional and an additional longitudinal series of 23 HGAIN biopsies preceding anal cancer (i.e., progressive HGAIN).For both devices analytical quality criteria were met. ASCL1 and ZNF582 methylation levels increased with increasing severity of disease (p < 6*10−8). Diagnostic performance for AIN3+ was 0.81. All cancers and virtually all progressive HGAIN were detected at 70% and 80% specificity.In conclusion, the ASCL1/ZNF582 methylation test (PreCursor-M AnoGYN (RUO)) was demonstrated to be highly robust and reproducible. Moreover, it had excellent diagnostic accuracy to detect AIN3+ and can potentially be used to guide HGAIN management.

A QbD Assisted Bioanalytical Method Development and Validation for Simultaneous Estimation of Montelukast and Bilastine by LC-MS Technique

This study describes how to use internal standards (IS) under the Analytical Quality by Design (AQbD) methodology to measure montelukast and bilastine in artificial rabbit plasma. The protein precipitation method was used for sample preparation and extraction. The chromatographic analysis was performed on the processed materials. The measurement range of the calibration was between 2 to 40 ng/mL for Bilastine and 1 to 20 ng/mL for montelukast. Optimizing mobile phase composition, flow rate, and pH were used to determine peak area and retention time. A significant reduction in method variability was observed as a result of the method of experimental design during optimization, and this enhanced the stability of the technique. A validation study demonstrated linearity, accuracy, precision, selectivity, sensitivity, and stability for estimating bilastine and montelukast in rabbit plasma using the developed method. The chemical composition of the drug was not altered during tests on its stability in human plasma. Overall, the investigations showed that the established approach is straightforward, reliable, and affordable for use in regular pharmacokinetic and bioequivalence research.

Stability-Indicating Liquid Chromatography Method for Rifaximin and LC-MS Characterization of its Potential Degradants

Rifaximin (RFX) is a structural analog of rifampin that has been shown to be a gastrointestinal-selective antibiotic with broad-spectrum antibacterial properties, a pronounced safety profile, and limited drug interactions. Crohn’s disease, diarrhea, hepatic encephalopathy, irritable bowel syndrome, and traveler’s diarrhea caused by non-invasive diarrheagenic Escherichia coli, can all be treated with rifaximin. FDA has designated RFX as an orphan drug for the treatment of hepatic encephalopathy. There is a substantial need for analytical quality monitoring of Rifaximin to ensure the safety and efficacy of treatment. To generate degradants, forced degradation study of the drug was carried out in acid, alkali, oxidative, thermal, and photolytic stress conditions. The optimum separation of the drug, and its degradants was achieved on an Inertsil ODS-3V C18 column (250 X 4.6 mm X 5 μm) under gradient elution conditions using, 10 mM potassium dihydrogen orthophosphate (pH 5.0 ± 0.05) as mobile phase A, and acetonitrile as mobile phase B, at a flow rate of 1.0 mL/min. The run time was 41 minutes and the detection wavelength was 258 nm. The method was validated in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human use Guidelines. The drug was stable in neutral hydrolysis, photo and dry heat degradation conditions. The percentage degradation observed during acid, alkali hydrolysis and oxidative stress conditions were 70.46, 15.11 and 24.18, respectively. The degradants were investigated by LC-MS which indicated the presence of four (m/z 784.2, 744.5, 784.3, 753.8), three (m/z 744.5, 784.3, 753.8) and five (m/z 772.4, 838.4, 744.5, 753.8, and 801.9) degradants in acid, alkali and oxidative stress conditions, respectively. The structures of degradants were elucidated using Liquid chromatography–mass spectrometry (LC-MS) and Liquid chromatography tandem mass spectrometry (LC-MS/MS) analyses.

RP HPLC-Based Method Development, Validation and Stability Indicating Assay of Levosulpiride in Bulk Drug Using Analytical Quality by Design Approach

RP HPLC-Based Method Development, Validation and Stability Indicating Assay of Levosulpiride in Bulk Drug Using Analytical Quality by Design Approach

Environmentally sustainable analytical quality by design aided RP-HPLC method for the estimation of brilliant blue in commercial food samples employing a green-ultrasound-assisted extraction technique

Abstract Brilliant blue FCF (E133) is a commonly employed azo synthetic dye in the food industry owing to its visually appealing color and widespread consumer acceptance. The health risks associated with the excessive use of brilliant blue necessitate prioritizing eco-friendly methods for its quantification. The purpose of this study is to develop and validate an analytical quality by design (AQbD) based eco-friendly high-performance liquid chromatography method adhering to the 12 principles of green chemistry followed by ultrasound-assisted extraction of food samples and confirming them using Fourier transform infrared spectroscopy. Rotatable central composite designs (CCDs) were utilized to optimize the chromatographic parameters. The separation was achieved on a Phenomenex column (Luna C18, 250 mm × 4.6 mm, i.d. 5 μm) employing ethanol and acetate buffer as a mobile phase in the ratio 25:75 (v/v) at a flow rate of 1 mL·min−1 with detection at 626 nm, which resulted in elution of brilliant blue at 2.692 min. The developed method fulfills the predetermined requirements of linearity, accuracy, sensitivity, and reproducibility at the specified working point. The green analytical procedure index, analytical eco scale, and analytical greenness metrics were used for assessing greenness, which yielded the most benign outcomes. In the future, this research could lead to the adoption and enhancement of eco-friendly robust AQbD methodologies for evaluating various food colorants, utilizing green solvents.

Analytical QBD Approach to Redefine the Quality of Pharmaceuticals: A Review

As per the present scenario traditional techniques of quality by testing of finished pharmaceutical products have proved to be unsatisfactory, although focus on 'Total quality assurance can be attained only by in-process testing and analysis. The Quality by Design (QbD) idea has already been established and applied in all nations that adhere to the International Conference on Harmonization Guidelines. The proposed ICH Guidelines Q8 for pharmaceutical development, Q9 for quality risk management, and Q10 for pharmaceutical quality systems offer a foundation for incorporating quality into the product. Other components are being added and integrated into the analytical method development process, including as Quality Risk Management, the Pharmaceutical Quality System, and Process Analytical Technology (PAT) guidelines. The Quality by Design (QbD) idea has already been established and applied in all nations that adhere to the International Conference on Harmonization Guidelines. The proposed ICH Guidelines Q8 for pharmaceutical development, Q9 for quality risk management, and Q10 for pharmaceutical quality systems offer a foundation for incorporating quality into the product. Other components are being added and integrated into the analytical method development process, including as Quality Risk Management, the Pharmaceutical Quality System, and Process Analytical Technology (PAT) guidelines. They are widely acknowledged in the business as AQbD (Analytical Quality by Design) ideas. This paper attempts to summarize QbD achievements to date, regulatory perspectives on QbD, a comparative examination of conventional and analytical QbD techniques in method development, and issues about its fundamental application. Keywords Quality by Design, Design of Experiments, Analytical Quality, Critical Quality Attributes Analytical Target Profile, Process Control

确定医疗旅游的目的地竞争力： 基于AHP-QFD框架的研究

This study investigates the competitiveness of Alanya, a medical tourism destination in Türkiye, and determines appropriate strategies using the analytical hierarchy process and quality function deployment. Data were collected from medical tourism experts to gain managerial insights into the factors affecting the competitiveness of medical tourism. The findings show that medical tourists primarily focus on medical factors such as competence of doctor and quality of treatment. The main strategies to strengthen competitiveness are to create a healthcare-free zone, to increase the number of accredited health care providers, and to encourage the involvement of doctors in academic research and ongoing training. For researchers interested in assessing competitiveness in medical tourism destinations, the study presents general determinants that should be considered in each destination. In addition, the findings show that each medical tourism destination should focus on its own determinants of medical tourism competitiveness when developing its marketing strategies. Finally, it shows that the analytical hierarchy process and quality function deployment approaches can be successfully applied in achieving destination competitiveness and strategic planning, with content validity and importance performance analysis.