Using multivariate adaptive regression splines to develop relationship between rock quality designation and permeability

The assessment of in situ permeability of rock mass is challenging for large-scale projects such as reservoirs created by dams,where water tightness issues are of prime importance.The in situ permeability is strongly related to the frequency and distribution of discontinuities in the rock mass and quantified by rock quality designation(RQD).This paper analyzes the data of hydraulic conductivity and discontinuities sampled at different depths during the borehole investigations in the limestone and sandstone formations for the construction of hydraulic structures in Oman.Cores recovered from boreholes provide RQD data,and in situ Lugeon tests elucidate the permeability.A modern technique of multivariate adaptive regression splines(MARS)assisted in correlating permeability and RQD along with the depth.In situ permeability shows a declining trend with increasing RQD,and the depth of investigation is within 50 m.This type of relationship can be developed based on detailed initial investigations at the site where the hydraulic conductivity of discontinuous rocks is required to be delineated.The relationship can approximate the permeability by only measuring the RQD in later investigations on the same site,thus saving the time and cost of the site investigations.The applicability of the relationship developed in this study to another location requires a lithological similarity of the rock mass that can be verified through preliminary investigation at the site.

A novel approach to structural anisotropy classification for jointed rock masses using theoretical rock quality designation formulation adjusted to joint spacing

Rock quality designation(RQD)has been considered as a one-dimensional jointing degree property since it should be determined by measuring the core lengths obtained from drilling.Anisotropy index of jointing degree(AI_(jd))was formulated by Zheng et al.(2018)by considering maximum and minimum values of RQD for a jointed rock medium in three-dimensional space.In accordance with spacing terminology by ISRM(1981),defining the jointing degree for the rock masses composed of extremely closely spaced joints as well as for the rock masses including widely to extremely widely spaced joints is practically impossible because of the use of 10 cm as a threshold value in the conventional form of RQD.To overcome this limitation,theoretical RQD(TRQD_(t))introduced by Priest and Hudson(1976)can be taken into consideration only when the statistical distribution of discontinuity spacing has a negative exponential distribution.Anisotropy index of the jointing degree was improved using TRQD_(t) which was adjusted to wider joint spacing by considering Priest(1993)’s recommendation on the use of variable threshold value(t)in TRQD_(t) formulation.After applications of the improved anisotropy index of a jointing degree(AI'_(jd))to hypothetical jointed rock mass cases,the effect of persistency of joints on structural anisotropy of rock mass was introduced to the improved AI'_(jd) formulation by considering the ratings of persistency of joints as proposed by Bieniawski(1989)’s rock mass rating(RMR)classification.Two real cases were assessed in the stratified marl and the columnar basalt using the weighted anisotropy index of jointing degree(W_AI'_(jd)).A structural anisotropy classification was developed using the RQD classification proposed by Deere(1963).The proposed methodology is capable of defining the structural anisotropy of a rock mass including joint pattern from extremely closely to extremely widely spaced joints.

A quality by design (QbD) case study on entericcoated pellets: Screening of critical variables and establishment of design space at laboratory scale

The study aims to prepare naproxen enteric-coated pellets(NAP-ECPs)by fluid-bed coating using QbD principle.Risk assessment was firstly performed by using failure mode and effect analysis(FMEA)methodology.A PlacketteBurman design was then used for assessment of the most important variables affecting enteric-coated pellets characteristics.A BoxeBehnken design was subsequently used for investigating the main,interactive,and quadratic effects of these variables on the response.By FMEA we discovered that eight factors should be considered to be high/important risk variables as compared with others.The responses of acid resistance and cumulative drug release were taken as critical quality attributes(CQAs).Pareto ranking analyses indicated that the coating weight gain(X_(7)),triethyl citrate percentage(X_(1))and glycerol monostearate percentage(X_(2))were the most significant factors affecting the selected responses out of the eight high-risk variables.Optimization with response surface method(RSM)further fully clarified the relationship between X_(7),X_(1),X_(2) and CQAs,and design space was established based on the constraints set on the responses.Due to the extreme coincidence of the predicted value generated by model with the observed value,the accuracy and robustness of the model were confirmed.It could be concluded that a promising NAP-ECPs was successfully designed using QbD approach in a laboratory scale.

QUALITY FUNCTION DEPLOYMENT IN BOTTOM-UP PROCESS FOR DESIGN REUSE

To deal with a bottom up process model for design reuses a specific extended house of quality(EHOQ)is proposed Two kinds of supported functions,basic supported functions and new supported functions,are defined.Two processes to determine two kinds of functions are presented A kind of EHOQ matrix for a company is given and its management steps are studied.

A strategy for population pharmaceutical quality assessment based on quality by design

From a regulatory perspective,drug quality consistency evaluation must concern different processes used for the same drug.In this study,an assessment strategy based on quality by design(QbD)was developed for population pharmaceutical quality evaluation.A descriptive analysis method based on QbD concept was first established to characterize the process by critical evaluation attributes(CEAs).Then quantitative analysis method based on an improved statistical process control(SPC)method was established to investigate the process indicators(PIs)in the process population,such as mean distribution,batch-to-batch difference and abnormal quality probability.After that rules for risk assessment were established based on the SPC limitations and parameters.Both the SPC parameters of the CEAs and the risk of PIs were visualized according to the interaction test results to obtain a better understanding of the population pharmaceutical quality.Finally,an assessment strategy was built and applied to generic drug consistency assessment,process risk assessment and quality trend tracking.The strategy demonstrated in this study could help reveal quality consistency from the perspective of process control and process risk,and further show the recent development status of domestic pharmaceutical production processes.In addition,a process risk assessment and population quality trend tracking provide databased information for approval.Not only can this information serve as a further basis for decisionmaking by the regulatory authority regarding early warnings,but it can also reduce some avoidable adverse reactions.With continuous addition of data,dynamic population pharmaceutical quality is meaningful for emergencies and decision-making regarding drug regulation.

Design Quality Is Essential to Excellent Project

Northwest Electric Power Design Institute (NWEPDI)was established in 1956. The institute undertakes the engineering exploration, survey and design of thermal electric power plant, conventional island of nuclear power plant, power transmission and substation projects, design of the 1st and 2nd class pressure vessels, electric power system planning, environmental protection engineering monitoring, assessment and design, various industrial and civil architectural design and the scicntific research and technical development tasks of corresponding specialities. The institute

Factors Affecting DMO’s Website Use Intention, and Visiting Intention: A SEM Model on the Impact of E-Destination Image and DMO’s Website Design

The aim of this study is to identify and analyze ways to increase usage of destination website and motivate website visitors’intention to actually visit the destination.The sample population is South Koreans who visit the VisitBritain website,the homepage of Britain’s national tourism agency.The data for this study were collected by a self-participated online survey on the blog of VisitBritain Korea,which is directly linked to the VisitBritain Korea website.Using structural equation modeling,six hypotheses were tested.The results show that the destination image on the destination marketing organization(DMO)website,quality of the destination website design including three dimensions(information quality,system quality,and service quality),and customers’satisfaction formed by high quality of the website design have a significant impact on website visitors’use intention and increase their visiting intention to the destination.Based upon the results of the analysis,managerial implications and areas for future research are proposed.

Design of experiments:how to develop and optimize drug delivery systems

Objective:Quality by design integration is exceedingly imperative for industries dealing with pharmaceuticals,but it diminishes product variability and delivers an extraordinary degree of assurance that the product would achieve the purpose for which it was formulated.The objective of the manuscript is to strengthen the understanding of the design of experimentation approach from the primary level.Hence,this review paper aims to get one experience with a course emphasizing product quality during its development process.Methods:The present work describes how experimental statistical designs can optimize the process.It is a strategy to improve the manufacturing of products and discuss the main factors involved in the production.The review describes different designs,advantages,disadvantages and design of experiments requirements concerning regulatory submissions.Results:Quality by design encourages the pharmaceutical industry to deal with risk management and proper understanding of products and manufacturing processes,assuring a good quality product.Having knowledge of quality by design and design of experiments in the formulation and process development will be beneficial for the optimization of drug delivery systems in upcoming times.Conclusion:Implementing quality by design at different phases in pharmaceutical manufacturing,the final product with a great degree of reproducible quality may be assured,depending upon experimental data.This contains valuable information in guiding new researchers about the importance and ways of using the design of experiments.

Growth behavior and resource potential evaluation of gas hydrate in core fractures in Qilian Mountain permafrost area, Qinghai-Tibet Plateau

The Qilian Mountain permafrost area located in the northern of Qinghai-Tibet Plateau is a favorable place for natural gas hydrate formation and enrichment,due to its well-developed fractures and abundant gas sources.Understanding the formation and distribution of multi-component gas hydrates in fractures is crucial in accurately evaluating the hydrate reservoir resources in this area.The hydrate formation experiments were carried out using the core samples drilled from hydrate-bearing sediments in Qilian Mountain permafrost area and the multi-component gas with similar composition to natural gas hydrates in Qilian Mountain permafrost area.The formation and distribution characteristics of multi-component gas hydrates in core samples were observed in situ by X-ray Computed Tomography(X-CT)under high pressure and low temperature conditions.Results show that hydrates are mainly formed and distributed in the fractures with good connectivity.The ratios of volume of hydrates formed in fractures to the volume of fractures are about 96.8%and 60.67%in two different core samples.This indicates that the fracture surface may act as a favorable reaction site for hydrate formation in core samples.Based on the field geological data and the experimental results,it is preliminarily estimated that the inventory of methane stored in the fractured gas hydrate in Qilian Mountain permafrost area is about 8.67×1013 m3,with a resource abundance of 8.67×108 m3/km2.This study demonstrates the great resource potential of fractured gas hydrate and also provides a new way to further understand the prospect of natural gas hydrate and other oil and gas resources in Qilian Mountain permafrost area.

Whole-process optimization for industrial production of glucosamine sulfate sodium chloride based on QbD concept

The double salt of glucosamine sulfate sodium chloride(glucosamine-SP) is an important pharmaceuticals ingredient for healing osteoarthritis. However, the study about its industrial production is rarely documented, let alone the optimization over the whole process to produce glucosamine-SP using glucosamine hydrochloride and anhydrous sodium sulfate as synthetic raw materials. In order to improve the production efficiency, this study screened the process parameters based on the concept of quality by design(QbD), optimized 13 operational parameters related to reaction and separation in the process, and finally proposed the mixed dropping process. The reaction conditions for the preparation of glucosamineSP were found as follows: the molar ratio of anhydrous sodium sulfate to glucosamine hydrochloride is 0.42, the mass ratio of water to glucosamine hydrochloride is is 2.0, the reaction temperature is 50 ℃ and the reaction time is 1 h. Through step-by-step scaling up following QbD, the mixed dropping process was successfully applied to achieve a trial production of 200 kg products satisfying national quality standards.In all, the results of this study have high technical value and guiding significance for the industrial mass production of glucosamine-SP.

Fluidised bed granulation of two APIs:QbD approach and development of a NIR in-line monitoring method

The study focused on the fluid-bed granulation process of a product with two active pharmaceutical ingredients,intended for coated tablets preparation and further transfer to industrial scale.The work aimed to prove that an accurate control of the critical granulation parameters can level the input material variability and offer a user-friendly process control strategy.Moreover,an in-line Near-Infrared monitoring method was developed,which offered a real time overview of the moisture level along the granulation process,thus a reliable supervision and control process analytical technology(PAT)tool.The experimental design’s results showed that the use of apparently interchangeable active pharmaceutical ingredients(APIs)and filler sorts that comply with pharmacopoeial specifications,lead to different end-product critical attributes.By adapting critical granulation parameters(i.e.binder spray rate and atomising pressure)as a function of material characteristics,led to granules with average sizes comprised in a narrow range of 280–320μm and low nongranulated fraction of under 5%.Therefore,the accurate control of process parameters according to the formulation particularities achieved the maintenance of product within the design space and removed material related variability.To complete the Quality by design(QbD)strategy,despite its limited spectral domain,the microNIR spectrometer was successfully used as a robust PAT monitoring tool that offered a real time overview of the moisture level and allowed the supervision and control of the granulation process.

Hot melt extrusion:An industrially feasible approach for casting orodispersible film

Over the recent few decades,many groups of formulation scientists are concentrating on rapid release dosage forms in oral cavity.Among all fast release dosage forms,orodispersible films are successful to attract pharmaceutical industry due to ease of formulation and extension patent life.Films are popular in patients too because of quick onset and user friendliness of dosage form.From the beginning,solvent casting has been selected as method of choice for manufacturing of orodispersible films.Solvent casting has been proved as a benchmark technology because of ease in product development,process optimization,process validation and technology transfer to production scale despite of some drawbacks like more number of unit operations involved and consumption of large quantity of solvents with controlled limits of organic volatile impurities in final formulation.The application of hot-melt extrusion(HME)in the pharmaceutical industry is consecutively increasing due to its proven innumerable advantages like solvent free continuous process with fewer unit operations and better content uniformity.Very few development activities has been initiated in the field of hot melt extruded orodispersible films so far.This extensive review covers detailed discussion of heavy duty industrial extruders,selection of downstream equipments,selection of excipients,common problems found in formulations and their remedies.Successive part of review addresses identification of critical quality attributes,quality target profile of product,criticality in selection of process parameters and material for substantial simulation in laboratory scale and production for successful technology transfer.

QbD Approach Method Development for Estimation of Dabigatran Etexilate along with Its Impurities and Identification of Degradants in Capsule Dosage Form

The concept of Quality by Design was demonstrated in the development of a stability-indicating assay and related substances method by HPLC for Dabigatran Etexilate Capsules dosage form. Method design, method evaluation, method control and life cycle management were explained by systematic flow chart. Analytical Target Product profile was defined. The method was developed using the Inertsil ODS-3V, 150 mm × 4.6 mm, 5 μm column using the gradient program with ammonium formate buffer as mobile phase A and acetonitrile as mobile phase B. Risk assessment was performed as part of method evaluation. Design of experiment tools was used to optimize the chromatographic conditions. A two-level Full Factorial Design along with Face Centered Central Composite design augmentation was employed and statistical analysis of the experimental data uncovered the significant influential of chromatographic factors. The design space and the contour plot suggest that the current center point parameters can be further modified, resulting in better acceptability of the response parameters. The performance of the optimized method was validated according to current ICH guidelines. Dabigatran Etexilate Capsules was subjected to various stress conditions like oxidative, acid, base, hydrolytic, thermal, humidity, and photolytic degradations and evaluated chromatograms at 220 nm. The degradation products were well separated from each other and main peak, demonstrating the stability-indicating power of the method. One of the major degradant impurities, which are forming in neutral hydrolysis stress condition, is isolated and characterized by using analytical techniques like IR, LC-MS and NMR. Degradation pathway for Dabigatran Etexilate was proposed based on forced degradation data along with reaction mechanism.

Overview of the Analytical Lifecycle of Supercritical Fluid Chromatography Methods

In recent times, the overall interest over Supercritical Fluid Chromatography (SFC) is truly growing within various domains but especially for pharmaceutical analysis. However, in the best of our knowledge modern SFC is not yet applied for drug quality control in the daily routine framework. Among the numerous reported SFC methods, none of them could be found to fully satisfy to all steps of the analytical method lifecycle. Thereby, the present contribution aims to provide an overview of the current and past achievements related to SFC techniques, with a targeted attention to this lifecycle and its successive steps. The included discussions were therefore structured accordingly and emphasizing the analytical method lifecycle in accord with the International Conference on Harmonisation (ICH). Recent and important scientific outputs in the field of analytical SFC, as well as instrumental evolution, qualification strategies, method development methodologies and discussions on the topic of method validation are reviewed.

The Contributions of Building Information Modelling to Sustainable Construction

Global concerns toward environmental issues have induced growing demand for new approaches in the construction because of its considerable impact on the environment and use of natural resources. Through using construction sustainability tools, methods and techniques, a greener design can be applied during various building phases. In this connection, it is argued that the analytical and integrated models applied by Building Information Modelling (BIM) may also facilitate this process to be performed more efficiently. BIM and construction sustainability are quite different initiatives, but both have received much attention in recent years in the architecture, engineering and construction (AEC) industry. A rigorous analysis of the interactions between them implies that a synergy exists which, if properly it is understood that can be helpful to reduce the environmental impacts of the AEC industry. A BIM-based design model can contribute to sustainability through its three main dimensions which are environmental, economic and social. In this paper, by reviewing the existing literature on BIM and construction sustainability and using a matrix to analyze construction sustainability dimensions and BIM functionalities a number of interactions have been discussed. It can be concluded that despite there are many improvements in implementation of BIM in environmental and economic aspects of sustainability, its potential impact on social dimension has not been explicitly explored hence further studies need to be undertaken in this area.

Establishment and reliability evaluation of the design space for HPLC analysis of six alkaloids in Coptis chinensis(Huanglian) using Bayesian approach

Coptis chinensis(Huanglian) is a commonly used traditional Chinese medicine(TCM) herb and alkaloids are the most important chemical constituents in it. In the present study, an isocratic reverse phase high performance liquid chromatography(RP-HPLC) method allowing the separation of six alkaloids in Huanglian was for the first time developed under the quality by design(Qb D) principles. First, five chromatographic parameters were identified to construct a Plackett-Burman experimental design. The critical resolution, analysis time, and peak width were responses modeled by multivariate linear regression. The results showed that the percentage of acetonitrile, concentration of sodium dodecyl sulfate, and concentration of potassium phosphate monobasic were statistically significant parameters(P < 0.05). Then, the Box-Behnken experimental design was applied to further evaluate the interactions between the three parameters on selected responses. Full quadratic models were built and used to establish the analytical design space. Moreover, the reliability of design space was estimated by the Bayesian posterior predictive distribution. The optimal separation was predicted at 40% acetonitrile, 1.7 g·m L-1of sodium dodecyl sulfate and 0.03 mol·m L-1 of potassium phosphate monobasic. Finally, the accuracy profile methodology was used to validate the established HPLC method. The results demonstrated that the Qb D concept could be efficiently used to develop a robust RP-HPLC analytical method for Huanglian.

Current approaches of nanomedicines in the market and various stage of clinical translation

Compared with traditional drug therapy,nanomedicines exhibit intriguing biological features to increase therapeutic efficiency,reduce toxicity and achieve targeting delivery.This review provides a snapshot of nanomedicines that have been currently launched or in the clinical trials,which manifests a diversified trend in carrier types,applied indications and mechanisms of action.From the perspective of indications,this article presents an overview of the applications of nanomedicines involving the prevention,diagnosis and treatment of various diseases,which include cancer,infections,blood disorders,cardiovascular diseases,immuno-associated diseases and nervous system diseases,etc.Moreover,the review provides some considerations and perspectives in the research and development of nanomedicines to facilitate their translations in clinic.

Regulatory considerations for animal studies of biomaterial products

Animal studies play a vital role in validating the concept,feasibility,safety,performance and efficacy of biomaterials products during their bench-to-clinic translation.This article aims to share regulatory considerations for animal studies of biomaterial products.After briefly emphasizing the importance of animal studies,issues of animal studies during biomaterial products’translation are discussed.Animal studies with unclear purposes,flawed design and poor reporting quality could significantly reduce the translation efficiency and create regulatory challenges.Regulatory perspectives on the purpose,principle,quality and regulatory science of animal studies are also presented.Animal studies should have clear purposes,follow principles of 3R+DQ(replacement,reduction,refinement,design and quality)and execute under an efficiently operating quality management system.With the advancement of regulatory science,National Medical Products Administration of China has been developing a series of standards and guidance documents on animal studies of medical devices.Case studies of making decisions on whether to conduct animal studies are provided in the end with drug-eluting stents as examples.In summary,animal studies of biomaterial products should pay close attention to the rationale,design and quality in order to achieve their purposes.