Applications of quality by design(QbD) and its tools in drug delivery

Quality by Test (Qb T) was the only way to guarantee the quality of drug products before FDA launches current Good Manufacturing Practice (c GMP)[1], which is an approach without clear understanding of the processes. In order to solve this problem,FDA generalized Quality by Design (QbD) in the field of pharmacy (2)In pharmaceutical industry, Qb D brings cost-efficiency and simplicity of manufacturing process into reality.

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.

Research on Key Points of Design of Standard Plants in Modern Industrial Parks Under the Background of Promoting the Development of New Quality Productive Forces

With the progress of science and technology and the acceleration of industrialization,the modern industrial park is an important carrier of industrial development.The importance of its standard plant design has become increasingly prominent.With the development of new quality productive forces as the background,this research deeply discusses the key points of standard plant design in modern industrial parks.This paper uses literature review and case analysis to systematically analyze the important role of standard plant design in developing new quality productive forces in modern industrial parks and puts forward suggestions for optimizing design.It is found that the rationality,intelligence,and environmental protection of plant design are the key factors affecting the development of new quality productive forces.The paper summarizes the core points of modern industrial park standard plant design to provide a reference for the future development of related industries.

Extraction process in Chuantieling(CTL) based on the quality by design(QbD) concept

Objective This study aimed to design and optimize the water extraction process for Chuantieling(喘贴灵,CTL)based on the concept of quality by design(QbD).Methods The single-factor experiments were used to select the best experimental points of CTL water extraction.On this basis,the transfer rate of ephedrine hydrochloride and sin-apine thiocyanate,and the yield of the extract were evaluated as the evaluation indicators.The liquid-solid ratio,extraction time,and pH value were selected as the main factors to carry out the Box-Behnken design(BBD).A mathematical model of the critical process parameters(CPPs)and critical quality attributes(CQAs)was established,the interaction between CQAs and CPPs was examined,and the CTL extraction process design space was established and optimized,which guaranteed the stability of the process.The high performance liquid chro-matography(HPLC)was used to analyze the main active compounds in the CTL extract.Results Through single-factor experiments,the best experimental parameters were found to be a liquid-solid ratio of 8∶1,extraction time of 90 min,pH value of 4,and extraction times of three.The experimental variance analysis results of the BBD showed that the P value of the re-gression model was less than 0.05,and the lack-of-fit value was greater than 0.01,indicating that the constructed model had good predictive ability.The operating space of the CPPs of the CTL water extraction process was combined with the actual production situation.In the pro-duction situation,the best extraction process was nine times of water addition,72 min of ex-traction time,and 4.5 of pH value.The HPLC results showed that the peak areas of ephedrine hydrochloride,sinapine thiocyanate,tetrahydropalmatine,methyl eugenol,cinnamaldehyde,and 6-gingerol in the CTL extract accounted for 0.94%,14.32%,0.78%,31.23%,0.34%,and 0.44%of the total peak area,respectively.Conclusion The water extraction process design space of CTL based on QbD was conducive to actual production operations,ensuring the stability of the process.

基于QbD理念的散偏汤提取工艺设计空间预测

目的:预测散偏汤提取工艺的设计空间。方法:基于质量源于设计和设计空间理念,采用鱼骨图结合失效模型与效应分析的方法确定提取次数、提取时间、加水倍量为散偏汤提取工艺的关键工艺参数,以阿魏酸、芥子碱硫氰酸盐、甘草苷、甘草酸的含量及出膏率为关键质量属性,采用Box-Behnken响应面法试验设计拟合数学模型,考察其相互关系,建立散偏汤提取工艺设计空间。结果:依据数学模型建立了散偏汤提取工艺设计空间,在此空间内取点验证,发现单个处方阿魏酸、芥子碱硫氰酸盐、甘草苷、甘草酸的质量分数分别为0.450‰、0.787‰、0.248‰、0.451‰,出膏率为23.83%,符合关键质量属性的要求。结论:建立的设计空间可为散偏汤放大生产和质量控制提供参考。

Application of quality by design in the current drug development

Quality by Test was the only way to guarantee quality of drug products before FDA launched current Good Manufacturing Practice. To clearly understand the manufacture processes, FDA generalized Quality by Design(QbD) in the field of pharmacy, which is based on the thorough understanding of how materials and process parameters affect the quality profile of final products. The application of QbD in drug formulation and process design is based on a good understanding of the sources of variability and the manufacture process. In this paper,the basic knowledge of QbD, the elements of QbD, steps and tools for QbD implementation in pharmaceutics field, including risk assessment, design of experiment, and process analytical technology(PAT), are introduced briefly. Moreover, the concrete applications of QbD in various pharmaceutical related unit operations are summarized and presented.

基于质量源于设计(QbD)理念优化黄精粗多糖制备工艺及抗氧化活性检测

试验旨在优化复合酶协同超声水提醇沉法制备黄精粗多糖(crude polysaccharide of po⁃lygahatous,CPP)的工艺并检测其体外抗氧化活性。试验以质量源于设计(qulity by design,QbD)理念为指导,以黄精多糖得率和含量为指标,应用Box-Behnken响应面设计法(BBD)对CPP制备工艺的关键因素:酶解温度、加酶量、超声时间、醇沉浓度进行优化;以维生素C(Vitamin C,VC)为对照,对CPP进行1,1-二苯基-2-三硝基苯肼(1,1-Diphenyl-2-picrylhydrazyl,DPPH)自由基和羟基(·OH)自由基清除能力的检测,评价CPP体外抗氧化活性。结果表明:CPP最佳制备工艺为酶解温度55℃,复合酶(纤维素酶∶果胶酶=1∶1)用量0.28%,超声时间50 min,醇沉浓度78%;采用该制备工艺,CPP的得率为(28.12±1.43)%,多糖含量为(33.74±1.32)%。不同浓度CPP能够有效清除DPPH自由基和抑制·OH的产生。由此可见,优化的CPP制备工艺稳定可行,且所制得的CPP具有一定的体外抗氧化活性。

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.

Product design on the basis of fuzzy quality function deployment

In the implementation of quality function deployment （QFD）, the determination of the target values of engineering characteristics is a complex decision process with multiple variables and multiple objectives that should trade off, and optimize all kinds of conflicts and constraints. A fuzzy linear programming model （FLP） is proposed. On the basis of the inherent fuzziness of QFD system, triangular fuzzy numbers are used to represent all the relationships and correlations, and then, the functional relationships between the customer needs and engineering characteristics and the functional correlations among the engineering characteristics are determined with the information in the house of quality （HoQ） fully used. The fuzzy linear programming （FLP） model aims to find the optimal target values of the engineering characteristics to maximize the customer satisfaction. Finally, the proposed method is illustrated by a numerical example.

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.

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.

Analytical quality-by-design approach for sample treatment of BSA-containing solutions

The sample preparation of samples conlaining bovine serum albumin（BSA）,e.g..as used in transdermal Franz diffusion cell（FDC） solutions,was evaluated using an analytical qualily-by-design（QbD）approach.Traditional precipitation of BSA by adding an equal volume of organic solvent,often successfully used with conventional HPLC-PDA,was found insufficiently robust when novel fused-core HPLC and/or UPLC-MS methods were used.In this study,three factors（acetonitrile（%）.formic acid（%） and boiling time（min）） were included in the experimental design to determine an optimal and more suitable sample treatment of BSAcontaining FDC solutions.Using a QbD and Derringer desirability（D） approach,combining BSA loss,dilution factor and variability,we constructed an optimal working space with the edge of failure defined as D〈0.9.The design space is modelled and is confirmed to have an ACN range of 83 ± 3% and FA content of 1 ±0.25%.

Fuzzy Design Method of Product Quality Robustness

In order to express information on the quality grade of product designed, the target value of product quality design was described with a fuzzy number in this paper. The rule of robust design with a fuzzy target was analyzed with fuzzy probability theory, then the principle and modeling method of fuzzy robust design for a high quality product were put forward. With this new method used, the high quality ratio of the product designed could be increased, and the ability to resist the influence of various disturbing factors and noise factors could be enhanced.

GMA material design and construction quality control for asphalt pavement of steel box girder: Case study of the Hong Kong–Zhuhai–Macao Bridge

To improve the quality of the Hong Kong–Zhuhai–Macao Bridge paving project,a new paving layer material,Guss-mastic asphalt(GMA),was proposed in this paper by combining the advantages of two types of cast asphalt mixtures:mastic asphalt(MA)and Guss asphalt(GA).Based on the characteristics of GMA,to simulate its actual production process,this study developed a small-simulated cooker mixing equipment.Moreover,the flow degree,60C dynamic stability,and impact toughness were proposed to be used to evaluate the construction and ease,high temperature stability,and fatigue resistance of GMA cast asphalt mixtures,respectively.Moreover,the quality control standards for GMA paving materials by indoor tests,field trial mix GMA material performance tests,and accelerated loading tests were finalized.The study showed that the developed simulated cooker yielded consistent mixing results in the same working environment as the engineering cooker device.Increasing the coarse aggregate incorporation rate,coarsening the mastic epure(ME)gradation composition,and using a smaller oil to stone ratio can reduce the flowability of the GMA materials to varying degrees.The four-point bending fatigue life and impact toughness of the different GMA materials are correlated well.A mobility of<20 s,60C dynamic stability of 400–800 times/mm,15C impact toughness of400 N⋅mm,and cooker car mixing temperature control standard of 210C–230C form an appropriate control index system for the design and production of GMA cast asphalt mixtures.Simultaneously,accelerated loading tests verified the accuracy and reliability of the quality control index system that has been used in the GMA paving project of the Hong Kong–Zhuhai–Macao Bridge deck and has achieved good application results.

Robust Design of Mixing Static and Dynamic Multiple Quality Characteristics

Increased market competition means that quality, cost and delivery time are crucial elements of modern production techniques. Taguchi’s robust design is the most powerful method available for reducing product cost, improving quality, and simultaneously reducing development time. Robust design aims to reduce the impact of noise on the product or process quality and leads to greater customer satisfaction and higher operational performance. The objective of robust design is to minimize the total quality loss in products or processes. The PQL model proposed by this paper simultaneously optimizes the static and dynamic problems by minimizing the total quality loss. Using the proposed PQL model and steps for optimization, the method addresses complex parameter design, which varies with the properties and objectives of the experimental data, to improve the product quality. The example of an electron beam surface hardening process is provided to demonstrate the implementation and usefulness of the proposed method.

Analysis and Design of Quality Management Platform for the Entire Process of Characteristic Software Talent Training

At the end of 2021 to create a new model of characteristic software talent training for independent and controllable key software fields,the Ministry of Education and the Ministry of Industry and Information Technology jointly approved the establishment of the first batch of 33 Characteristic Pilot Schools of software.As a member of characteristic software schools,the HIT School of Software has been approved and will focus on the construction of 2 characteristic directions,which are large-scale industrial software and industrial professional application software.In order to achieve the goal,it is urgent to develop a comprehensive management platform to control the entire process of talent training,so that we can standardize,modelling,and digitized the entire process of characteristic software talent training.By relating all aspects of student training with and implementing the ability-index mechanisms,we will continuously collect big-data of the entire process of student growth,and generate multidimensional student ability portraits for evaluating the effect of talent training,and adjust as well as optimizing the growth path for students themselves during their studying.Employers will be able to identify talents accurately and provide effective reference for colleges to adjust training plans.This paper will analyze the needs of the platform,provide demand analysis of the platform,extract the correlation model between training,conclude the relations between ability-index activities and ability indicators,and give a reasonable overall system design scheme.

The pathway analysis for the cultivation of students＇ quality in the process of Art design major in colleges

With the metabolic production of human society and changing lifestyles, higher education comes up new demands for teaching about art and design＇ s specialty. Art and design specialty in university teaching will face significant new reforms. Modernization of teaching of art and design specialty is the comprehensive requirements for all types of talents, it regards improvement of teaching quality and efficiency as the guide and it is the theoretical basis of the principles and policies of higher education in our country, therefore, to strengthen the theoretical teaching of art and design specialty＇ s education, and the emphasis on students professional skills training and cultivation of basic quality become a key reform of teaching theory. This article makes the present situation of effective art and design specialty＇ s teaching in our country and makes deep analysis on how to strengthen the art and design specialty teaching in our higher schools.

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

A Robust Design Method in Product Quality Applications

In order to express information on the quality grade of product designed, thetarget value of product quality design was described with a fuzzy number in this paper. Analternative to Taguchi's, the robustness application design method has been recently presented.However, neither Taguchi's method nor the alternative method is capable of dealing satisfactorilywith the frequently encountered situations in which all the noise variables cannot be studiedsimultaneously. Based on the ideas from response surface modeling, linear models theory, and randomeffects models, we provide a method for estimation in the robustness application design method inproduct quality applications. With this new method used, the high-quality ratio of the productdesigned could be increased, and the ability to resist the influence of various disturbing factorsand noise factors could be enhanced.